Lysine based compounds

ABSTRACT

The present invention provides lysine based compounds of the formula; 
     
       
         
         
             
             
         
       
     
     and when the compound of formula I comprises an amino group, pharmaceutically acceptable ammonium salts thereof, wherein R 1  may be, for example, (HO) 2 P(O)—, (NaO) 2 P(O)—, alkyl-CO— or cycloalkyl-CO—, wherein X may be, for example, F, Cl, and Br, and wherein R 2  and R 3  are as defined herein.

TECHNICAL FIELD OF THE INVENTION

This invention relates to lysine based compounds which present goodsolubility, and bioavailability. More particularly, the presentinvention relates to lysine based compounds having a physiologicallycleavable unit, whereby upon cleavage of the unit, the compound is ableto release an HIV protease inhibitor. The compounds and pharmaceuticalcompositions of the present invention are particularly well suited fordecreasing the pill burden and increasing patient compliance.

BACKGROUND OF THE INVENTION

Inhibitors of the HIV viral protease have been developed relativelyrecently and t heir u se began only in 1996. Currently, they areconsidered the most effective drugs against HIV infection.Unfortunately, most current proteases inhibitors are relatively largehydrophobic molecules that possess rather low bioavailability. A highpill burden is therefore required to attain the therapeutic dose in apatient. This is a deterrent, which too often results in patientnon-compliance and inadequate treatment results. This situation leads tosub-optimal therapeutic drug concentration that in turns leads to thedevelopment of HIV resistant strains. Consequently, there is an urgentneed to improve the solubility and bioavailability of proteasesinhibitors.

Examples of improved compounds have been developed in the form ofprodrugs of aspartyl protease inhibitors such as described, for example,in U.S. Pat. No. 6,436,989 to Hale et al, the entire content of which isincorporated herein by reference. This patent shows a novel class ofmolecules characterized by favourable aqueous solubility, high oralbioavailability and facile in vivo generation of the active ingredient.However, it is well known that HIV has the ability to develop resistanceto the currently available drugs. Thus, there is a need for alternativeHIV protease inhibitors active towards wild-type and resistant viralstrains. Thus, molecules derived from current HIV protease inhibitorsshowing enhanced solubility and bioavailability is desirable to fightresistant viral strains.

A unique class of aromatic derivatives which are inhibitors of aspartylproteases is described in U.S. Pat. No. 6,632,816 to Stranix et al, theentire content of which is incorporated herein by reference. This patentincludes, more particularly, N,-synthetic amino acid substitutedL-lysine derivatives possessing potent aspartyl protease inhibitoryproperties. However, it would be advantageous to improve thesederivatives by enhancing aqueous solubility and bioavailability in orderto reduce the pill burden and to favour patient's compliance. Since itis challenging to generate active protease inhibitors, specificallytoward wild-type and resistant strains, the formation of derivatives oforiginal HIV protease inhibitors such as inhibitors described in U.S.Pat. No. 6,632,816 to Stranix et al, known to be active toward resistantstrains represents a viable route with considerable advantages. Moreparticularly, generation of compounds with enhanced aqueous solubility,bioavailability, time of duration and formulation properties along withother advantages is desirable in the development of an effective drug.

SUMMARY OF THE INVENTION

The present invention provides novel lysine based compounds originatingfrom a class of derivatives that are potent aspartyl protease inhibitorsand pharmaceutically acceptable derivatives thereof. These compounds mayreadily be cleaved in vivo to release the active ingredient. The activeingredient has an affinity for aspartyl proteases, in particular, HIV-1aspartyl protease (U.S. Pat. No. 6,632,816). The active ingredients alsopresent potent antiviral activity when tested on non-mutated HIV-1 viralstrain (NL4.3 as the wild type virus) as well as several mutant strains.Therefore, the compounds of the present invention may be useful as amean to increase solubility and improving bioavailability of the activeingredient (protease inhibitor). The compounds of the present inventionmay be used alone or in combination with other therapeutic orprophylactic agents for the treatment or prophylaxis of HIV infection.The compounds of the present invention possess good solubility andbioavailability and may be orally administered as aqueous solution.

It is the main objective of this invention to provide an improved classof lysine based compounds that are able to release an aspartyl proteaseinhibitor, and particularly, HIV aspartyl protease inhibitors. Lysinebased compounds of the present invention may have a cleavable unit,whereby upon cleavage of the unit the compound is able to release an HIVprotease inhibitor. The present invention also provides pharmaceuticalcompositions comprising lysine based compounds described herein.

Therefore the present invention provides in one aspect thereof, lysinebased compounds which upon in vivo physiological conditions (e.g.,metabolic, enteric and/or gastrointestinal conditions, etc.) allow therelease of a protease inhibitor (e.g., aspartyl protease inhibitor). Thecompounds of the present invention may serve as means for improving thesolubility and/or bioavailability of the protease inhibitors andtherefore may reduce the pill burden and may favour patient'scompliance.

The compounds of the present invention may have, for example, a (e.g.,physiologically) cleavable (e.g., hydrolysable) bond or unit which uponcleavage of the cleavable bond or unit generates a protease inhibitor(e.g., an active protease inhibitor).

The protease inhibitor may act on a spartyl protease of HIV-1 includingmutated and n on-mutated HIV-1 viral strain (e.g., NL4.3) or on proteaseof HIV-2 (mutated or non-mutated) or even on protease of related virus(SIV, etc.). The compounds of the present invention may be used alone orin combination with other therapeutic or prophylactic agents for thetreatment or prophylaxis of, for example, an HIV infection.

The compounds and the pharmaceutical compositions of the presentinvention may release the protease inhibitor (active ingredient) in vivoand thereby may inhibit (e.g., in vivo) the activity of HIV aspartylprotease, an enzyme essential for virus maturation and infectivity. Thecompounds and the pharmaceutical compositions of the present inventionmay possess higher bioavailability and may also be apt to reduce dosagesneeded for inhibition and consequently may improve treatment ofHIV-infected patients.

The present invention in accordance with one aspect thereof provides acompound (e.g. a compound able to generate an HIV protease inhibitor) offormula I:

pharmaceutically acceptable salts and derivatives thereof (e.g., forexample, when the compound of the present invention comprises an aminogroup, the pharmaceutically acceptable salt may be an ammonium salt),wherein n may be, for example, 3 or 4,wherein X and Y, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₄R₅,—NHCOR₄, —OR₄, —SR₄, —COOR₄, —COR₄, and —CH₂OH or X and Y togetherdefine an alkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O— and an ethylenedioxy group offormula —OCH₂CH₂O—,wherein R₆ may be selected, for example, from the group consisting of astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof,P wherein R₃ may be selected, for example, from the group consisting ofH, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl groupof 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and agroup of formula R_(3A)—CO—, wherein R_(3A) may be selected, forexample, from the group consisting of a straight or branched alkyl groupof 1 to 6 carbon atoms (e.g. methyl, ethyl-, propyl, iso-propyl, butyl,iso-butyl, tert-butyl, tert-butyl-CH₂—, etc.), a cycloalkyl group having3 to 6 carbon atoms (e.g. cyclopropyl-, cyclohexyl- etc.), acycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl partthereof and 1 to 3 carbon atoms in the alkyl part thereof, (e.g.cyclopropyl-CH₂—, cyclohexyl-CH₂—, etc.), an alkyloxy group of 1 to 6carbon atoms (e.g. CH₃O—, CH₃CH₂O—, iso-butylO-, tert-butylO-(Boc),etc.), tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃,ppyrrolidinyl, piperidinyl, 4-morpholinyl, CH₃O₂C—, CH₃O₂CCH₂—,Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl, 4-hydroxyphenyl,4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—, (CH₃CH₂CH₂)₂N—,HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—, 2-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X′ and Y′, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₄R₅, —NHCOR₄, —OR₄,—SR₄, —COOR₄, —COR₄ and —CH₂OH,wherein R₄ and R₅, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkylgroup of 3 to 6 carbon atoms,wherein R₂ may be selected, for example, from the group consisting of adiphenylmethyl group of formula IV

a naphthyl-1-CH₂— group of formula V

a naphthyl-2-CH₂— group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH₂— group of formula VIII

and wherein R₁ may be a cleavable unit (e.g., a physiologicallycleavable unit), whereby upon cleavage of the unit, the compoundreleases a protease inhibitor (an HIV protease inhibitor), provided thatR₁ is not H. For example, R₁ may be an enzymatically or metabolicallycleavable unit or hydrolysable bond which may be cleaved under entericand/or gastrointestinal conditions (pH) or other physiologicalconditions.

In accordance with the present invention, R₁ may be selected, forexample, from the group consisting of (HO)₂P(O) and (MO)₂P(O), wherein Mis an alkali metal (e.g. Na, K, Cs, etc) or alkaline earth metal (Ca,Mg, etc.).

Further in accordance with the present invention, R₁ may be a group offormula R_(1A)—CO—, wherein R_(1A) may be selected, for example, fromthe group consisting of a straight or branched alkyl group of 1 to 6carbon atoms (e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,tert-butyl, tert-butyl-CH₂—, etc.), a cycloalkyl group having 3 to 6carbon atoms (e.g. cyclopropyl-, cyclohexyl- etc.), a cycloalkylalkylgroup having 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to3 carbon atoms in the alkyl part thereof, (e.g. cyclopropyl-CH₂—,cyclohexyl-CH₂—, etc.), an alkyloxy group of 1 to 6 carbon atoms (e.g.CH₃O—, CH₃CH₂O—, iso-butylO-, tert-butylO— (Boc), etc.), —CH₂OH,CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 2-hydroxyphenyl,3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—, (CH₃)₂CHCH(NH₂)—,HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, aphenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X′, Y′, R₄ and R₅ are as defined herein.

The present invention further provides in another aspect a compound offormula II,

pharmaceutically acceptable salts and derivatives thereof (e.g., forexample, when the compound of the present invention comprises an aminogroup, the pharmaceutically acceptable salt may be an ammonium salt),wherein n may be 3 or 4,wherein X and Y, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₄R₅,—NHCOR₄, —OR₄, —SR₄, —COOR₄, —COR₄, and —CH₂OH or X and Y togethertogether define an alkylenedioxy group selected from the groupconsisting of a methylenedioxy group of formula —OCH₂O— and anethylenedioxy group of formula —OCH₂CH₂O—,wherein R₆ may be selected, for example, from the group consisting of astraight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3to 6 carbon atoms, a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof,wherein R₃ may be selected, for example, from the group consisting of H,a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and agroup of formula R_(3A)—CO—, wherein R_(3A) may be selected, forexample, from the group consisting of a straight or branched alkyl groupof 1 to 6 carbon atoms (e.g. methyl, ethyl-, propyl, iso-propyl, butyl,iso-butyl, tert-butyl, tert-butyl-CH₂—, etc.), a cycloalkyl group having3 to 6 carbon atoms (e.g. cyclopropyl-, cyclohexyl- etc.), acycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl partthereof and 1 to 3 carbon atoms in the alkyl part thereof, (e.g.cyclopropyl-CH₂—, cyclohexyl-CH₂—, etc.), an alkyloxy group of 1 to 6carbon atoms (e.g. CH₃O—, CH₃CH₂O—, iso-butylO-, tert-butylO-(Boc),etc.), tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃, —CH₂CH₂CF₃,ppyrrolidinyl, piperidinyl, 4-morpholinyl, CH₃O₂C—, CH₃O₂CCH₂—,Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl, 4-hydroxyphenyl,4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—, (CH₃CH₂CH₂)₂N—,HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—, 2-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X′ and Y′, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkcylgroup of 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₄R₅, —NHCOR₄,—OR₄, —SR₄, —COOR₄, —COR₄ and —CH₂OH,wherein R₄ and R₅, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, and a cycloalkylgroup of 3 to 6 carbon atoms,wherein R₂ may be selected from the group consisting of a diphenylmethylgroup of formula IV

a naphthyl-1-CH₂— group of formula V

a naphthyl-2-CH₂— group of formula VI

a biphenylmethyl group of formula VII

and an anthryl-9-CH₂— group of formula VIII

and wherein R₁ may be a physiologically cleavable unit, whereby uponcleavage of the unit the compound may be able to release a proteaseinhibitor, provided that R₁ is not H.

In accordance with the present invention, R₁ may be selected, forexample, from the group consisting of (HO)₂P(O) and (MO)₂P(O), wherein Mis an alkali metal (e.g. Na, K, Cs, etc) or alkaline earth metal (Ca,Mg, etc.).

Further in accordance with the present invention R₁ may be a group offormula R_(1A)—CO—,

wherein R_(1A) may be selected from the group consisting of a straightor branched alkyl group of 1 to 6 carbon atoms (e.g. methyl, ethyl,propyl, iso-propyl, butyl, iso-butyl, tert-butyl, tert-butyl-CH₂—,etc.), a cycloalkyl group having 3 to 6 carbon atoms (e.g. cyclopropyl-,cyclohexyl- etc.), a cycloalkylalkyl group having 3 to 6 carbon atoms inthe cycloalkyl part thereof and 1 to 3 carbon atoms in the alkyl partthereof, (e.g. cyclopropyl-CH₂—, cyclohexyl-CH₂—, etc.), an alkyloxygroup of 1 to 6 carbon atoms (e.g. CH₃O—, CH₃CH₂O—, iso-butylO-,tert-butylO— (Boc), etc.), —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—,HO₂CCH₂—, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,(CH₃)₂NCH₂—, (CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—,2-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,1-methyl-1,4-dihydro-3-pyridyl, 2-pyrazinyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl groupof formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula,

wherein X′, Y′, R₄ and R₅ are as defined herein.

In a further aspect, the present invention provides a compound offormula IIa;

pharmaceutically acceptable salts and derivatives thereof (e.g., forexample, when the compound of the present invention comprises an aminogroup, the pharmaceutically acceptable salt may be an ammonium salt),wherein X and Y, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₄R₅,—NHCOR₄, —OR₄, —SR₄, —COOR₄, —COR₄, and —CH₂OH or X and Y togetherdefine an alkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O— and an ethylenedioxy group offormula —OCH₂CH₂O—,wherein X′ and Y′, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₄R₅, —NHCOR₄, —OR₄,—SR₄, —COOR₄, —COR₄ and —CH₂OH,and wherein n, R₁, R₃, R₄, R₅ and R₆ are as defined herein.

In an additional aspect, the present invention provides a compound offormula IIb

pharmaceutically acceptable salts and derivatives thereof (e.g., forexample, when the compound of the present invention comprises an aminogroup, the pharmaceutically acceptable salt may be an ammonium salt),wherein X and Y, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₄R₅,—NHCOR₄, —OR₄, —SR₄, —COOR₄, —COR₄, and —CH₂OH or X and together definean alkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O— and an ethylenedioxy group offormula —OCH₂CH₂O—,wherein X′ and Y′, the same or different, may be selected, for example,from the group consisting of H, a straight alkyl group of 1 to 6 carbonatoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl groupof 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₄R₅, —NHCOR₄, —OR₄,—SR₄, —COOR₄, —COR₄ and —CH₂OH,and wherein n, R₁, R₃, R₄, R₅ and R₆ are as defined herein.

In yet an additional aspect, the present invention provides a compoundof formula IIc

pharmaceutically acceptable salts and derivatives thereof (e.g., forexample, when the compound of the present invention comprises an aminogroup, the pharmaceutically acceptable salt may be an ammonium salt),and wherein n, X, Y, X′, Y′, R₁, R₃, R₄, R₅ and R₆ are as definedherein.

In another aspect, the present invention relates to a compound offormula IIA;

wherein Y, n, R₁, R₂, R₃, X′ and Y′ are as defined herein. In accordancewith the present invention, R₁ may be, for example, (HO)₂P(O) or(NaO)₂P(O). Further in accordance with the present invention, n may be4. Y may be, for example, H. R₃ may be, for example, CH₃O—CO. R₂ may be,for example, a diphenylmethyl group of formula IV, where X′ and Y′ maybe, for example H,

Therefore, compounds of formula IIA′ as well as pharmaceuticallyacceptable salts and derivatives thereof are encompassed by the presentinvention,

such as, for example, compound of formula IIA′ wherein R₁ is (HO)₂P(O)or, compound of formula IIIA′ wherein R₁ is (NaO)₂P(O).

In yet another aspect, the present invention relates to a pharmaceuticalcomposition comprising at least one compound of formula I, II, IIa, IIb,IIc, IIA, IIIA′ or combination of compounds of formula I, II, IIa IIb,IIc, IIA and/or IIA′. The pharmaceutical composition may comprise apharmaceutically acceptable carrier. The pharmaceutical composition maycomprise, for example, a pharmaceutically effective amount of such oneor more compounds or as applicable, pharmaceutically acceptable ammoniumsalts thereof.

For example, pharmaceutical composition of the present invention maycomprise one or more of the following compounds;

-   -   a compound of formula IIa wherein n is 4, R₁ is (HO)₂P(O), X is        4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        CH₃O—CO,    -   a compound of formula IIa wherein n is 4, R₁ is (NaO)₂P(O), X is        4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        CH₃O—CO,    -   a compound of formula IIa wherein n is 4, R₁ is (HO)₂P(O), X is        4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        CH₃CO,    -   a compound of formula IIa wherein n is 4, R₁ is (HO)₂P(O), X is        4-NH₂, Y is 3-F, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        CH₃O—CO,    -   a compound of formula IIa wherein n is 4, R₁ is CH₃CO, X is        4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        CH₃O—CO,    -   a compound of formula IIa wherein n is 4, R₁ is 3-pyridyl-CO, X        is 4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        CH₃O—CO,    -   a compound of formula IIa wherein n is 4, R₁ is (CH₃)₂NCH₂CO, X        is 4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        CH₃O—CO,    -   a compound of formula IIa wherein n is 4, R₁ is        (CH₃)₂CHCH(NH₂)CO, X is 4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is        iso-butyl and R₃ is CH₃O—CO,    -   a compound of formula IIb wherein n is 4, R₁ is (HO)₂P(O), X is        4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        CH₃O—CO and wherein the naphthyl group is a naphthyl-2-CH₂        group,    -   a compound of formula IIb wherein n is 4, R₁ is (HO)₂P(O), X is        4-NH₂, Y is H, X′ is H, Y′ is H, R₆ is iso-butyl and R₃ is        4-morpholine-CO and wherein the naphthyl group is a        naphthyl-1-CH₂ group, or    -   a combination of any of the above mentioned compounds.

In an additional aspect, the present invention relates to the use of atleast one compound of formula I, II, IIa, IIb, IIc, IIA, IIA′ orcombination of compounds of formula I, II, IIa IIb, IIc, IIA and/or IIA′or pharmaceutically acceptable salts or derivatives thereof (as well astheir combinations) in the manufacture of a drug (or pharmaceuticalcomposition) for the treatment or prevention of an HIV infection.

In a further aspect, the present invention relates to the use of atleast one compound of formula I, II, IIa, IIb, IIc, IIA, IIA′ orcombination of compounds of formula I, II, IIa IIb, IIc, IIA and/or IIA′or pharmaceutically acceptable salts or derivatives thereof in thetreatment or prevention of an HIV infection in a mammal in need thereofor for delaying the apparition of AIDS.

In yet a further aspect, the present invention relates to a method oftreating or preventing an HIV infection (or for delaying the apparitionof AIDS) comprising administering at least one compound of formula I,II, IIa, IIb, IIc, IIA, IIA′ or combination of compounds of formula I,II, IIa IIb, IIc, IIA and/or IIA′ or pharmaceutically acceptable saltsor derivatives thereof to a mammal in need thereof.

In another aspect the present invention relates to a compound of formulaI, II, IIa, IIb, IIc, IIA or IIA′, pharmaceutically acceptable salts orderivatives thereof for use in the treatment or prevention of an HIVinfection.

In yet a further aspect the present invention relates to a method offabricating a lysine based compound using any one of the compoundsdisclosed in U.S. Pat. No. 6,632,816 to Stranix et al. or a method offabricating a compound able to generate any one of the disclosed in U.S.Pat. No. 6,632,816 to Stranix et al. upon cleavage of a (in vivo)cleavable unit.

The compounds listed herein are exemplary embodiments of the presentinvention and it is to be understood that the present invention is notrestricted to these compounds only.

The term “pharmaceutically effective amount” refers to an amounteffective in treating or preventing HIV infection in a patient or forreducing or eliminating symptoms of AIDS. It is also to be understoodherein that a “pharmaceutically effective amount” may be construed as anamount giving a desired therapeutic effect, either taken into a singleor multiple doses or in any dosage or route or taken alone or incombination with other therapeutic agents. In the case of the presentinvention, a “pharmaceutically effective amount” may be understood as anamount having an inhibitory effect on HIV (HIV-1 and HIV-2 as well asrelated viruses (e.g., HTLV-I and HTLV-II, and simian immunodeficiencyvirus (SIV))) infection cycle (e.g., inhibition of replication,reinfection, maturation, budding etc.) and on any organism which rely onaspartyl proteases for its life cycle. An inhibitory effect is to beunderstood herein as an effect such as a reduction in the capacity of anorganism (e.g. HIV) to reproduce itself (replicate), to re-infectsurrounding cells, etc, or even a complete inhibition (or elimination)of an organism.

The terms “HIV protease” and “HIV aspartyl protease” are usedinterchangeably and include the aspartyl protease encoded by the humanimmunodeficiency virus type 1 or 2.

The term “prophylactically effective amount” refers to an amounteffective in preventing HIV infection in a patient. As used herein, theterm “patient” refers to a mammal, including a human.

The terms “pharmaceutically acceptable carrier”, “pharmaceuticallyacceptable adjuvant” and “physiologically acceptable vehicle” refer to anon-toxic carrier or adjuvant that may be administered to a patient,together with one or more compounds of the present invention, and whichdoes not destroy the pharmacological activity thereof.

The present invention provides pharmaceutically acceptable derivativesof the compounds of formula I (such as compounds of formulae II, IIa,IIb, IIc, IIA and IIA′) and where applicable pharmaceutically acceptablesalts thereof such as, for example, ammonium salts. A “pharmaceuticallyacceptable derivative” means any pharmaceutically acceptable salt,ester, or salt of such ester, of a compound of this invention or anyother compound which, upon administration to a recipient, is capable ofproviding (directly or indirectly) a compound of this invention or anantivirally active metabolite or residue thereof.

It is to be understood herein that a “straight alkyl group of 1 to 6carbon atoms” includes for example, methyl, ethyl, propyl, butyl,pentyl, hexyl.

It is to be understood herein that a “branched alkyl group of 3 to 6carbon atoms” includes for example, without limitation, iso-butyl,tert-butyl, 2-pentyl, 3-pentyl, etc.

It is to be understood herein, that a “cycloalkyl group having 3 to 6carbon” includes for example, without limitation, cyclopropyl,cyclobutyl, cyclopentyl, cyclocyclohexyl (i.e., C₆H₁₁).

Salts derived from appropriate bases include alkali metal (e.g.,sodium), alkaline earth metal (e.g., magnesium), ammonium and N—(C₁₋₄alkyl)₄ ⁺ salts.

The compounds of this invention contain one or more asymmetric carbonatoms and thus may occur as racemates and racemic mixtures, singleenantiomer, diastereomeric mixtures and individual diastereoisomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be of the R or Sconfiguration.

Pharmaceutically acceptable salts of the compounds of this inventioninclude those derived from pharmaceutically acceptable inorganic andorganic acids and bases. Examples of such acid salts include: acetate,adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylhydrogensulfate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycollate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthylsulfonate, nicotinate, nitrate, oxalate,pamoate, pectinate, perchlorate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, salicylate, succinate,sulfate, tartrate, thiocyanate, tosylate, and undecanoate.

This invention also envisions the quaternization of any basic nitrogencontaining groups of the compounds disclosed herein. The basic nitrogenmay be quaternized with any agents known to those of ordinary skill inthe art including, for example, lower alkyl halides, such as methyl,ethyl, propyl and butyl chlorides, bromides and iodides; dialkylsulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, and aralkyl halides including benzyl and phenethylbromides. Water or oil-soluble or dispersible products may be obtainedby such quaternization.

It is to be understood herein, that if a “range” or “group ofsubstances” is mentioned with respect to a particular characteristic(e.g., temperature, concentration, time and the like) of the presentinvention, the present invention relates to and explicitly incorporatesherein each and every specific member and combination of sub-ranges orsub-groups therein whatsoever. Thus, any specified range or group is tobe understood as a shorthand way of referring to each and every memberof a range or group individually as well as each and every possiblesub-ranges or sub-groups encompassed therein; and similarly with respectto any sub-ranges or sub-groups therein. Thus, for example,

-   -   with respect to the number of carbon atoms, the mention of the        range of 1 to 6 carbon atoms is to be understood herein as        incorporating each and every individual number of carbon atoms        as well as sub-ranges such as, for example, 1 carbon atoms, 3        carbon atoms, 4 to 6 carbon atoms, etc.    -   with respect to reaction time, a time of 1 minute or more is to        be understood as specifically incorporating herein each and        every individual time, as well as sub-range, above 1 minute,        such as for example 1 minute, 3 to 15 minutes, 1 minute to 20        hours, 1 to 3 hours, 16 hours, 3 hours to 20 hours etc.;    -   and similarly with respect to other parameters such as        concentrations, elements, etc. . . .

It is in particular to be understood herein that the compound formulaeeach include each and every individual compound described thereby aswell as each and every possible class or sub-group or sub-class ofcompounds whether such class or sub-class is defined as positivelyincluding particular compounds, as excluding particular compounds or acombination thereof; for example an exclusionary definition for theformula (e.g. I) may read as follows: “provided that when one of A and Bis —COOH and the other is H, —COOH may not occupy the 4′ position”.

It is also to be understood herein that “g” or “gm” is a reference tothe gram weight unit and “C”, or “° C.” is a reference to the Celsiustemperature unit.

The compounds of the present invention may easily be prepared usingconventional techniques from readily available starting materials. Thedetailed descriptions of these approaches are presented, for example, inschemes 1 to 5 discussed below.

Scheme 1 illustrates a generic example for the preparation of thephosphate monoester III derived from a primary alcohol (see I), acompound of HIV protease inhibitors (see example 1 (step G and H) in theexperimental portion of this document for a specific example of thissynthesis).

Note:

a) R₂ and R₃ are as defined herein.

The synthesis of phosphate monoester III may use a HIV aspartyl proteaseinhibitor (I, see U.S. Pat. No. 6,632,816) as the starting material. Thediethyl phosphotriester II was obtained in good yield upon treatmentwith diethyl chlorophosphate and sodium hydride in a mixture oftetrahydrofuran and triethylphosphate. Then, addition of trimethysilylbromide in dichloromethane (DCM) gave compound III in good to excellentyields.

Scheme 1A represents another generic example for the preparation of thephosphate monoester IIIA derived from a primary alcohol (see IA), acompound of HIV protease inhibitors.

Note:

a) n, X, Y, R₂, R₃ and R₆ are as defined herein.

The synthesis of phosphate monoester IIIA is performed as described forthe preparation of III (scheme 1).

Scheme 2 illustrates a generic example for the preparation of thephosphate monoester III, a compound of HIV protease inhibitors, with adifferent approach starting from (3S)-3-isobutylamino-azepan-2-one (IV).

Note:

a) R₂ and R₃ are as defined herein.

As shown in scheme 2, the phosphate monoester derivative III wasobtained from (3S)-3-isobutylamino-azepan-2-one (IV) in a seven-stepreaction sequence. Initially, (2S)-3-isobutylamino-azepan-2-one (IV) wassulfonated with 4-acetamidobenzenesulfonyl chloride in the presence oftriethylamine in dichloromethane to give compound V in excellent yields.The derivative VI was obtained quantitatively upon treatment of V withdi-tert-butyl pyrocarbonate and DMAP in acetonitrile. The reductive ringopening with sodium borohydride in ethanol lead to key intermediates VIIin good yield. The diethyl phosphotriester VIII was obtained in goodyield upon treatment with diethyl chlorophosphate and sodium hydride ina mixture of tetrahydrofuran and triethylphosphate. The Boc protectivegroups were removed upon treatment with HCl in ethanol to give compoundIX quantitatively (T. W. Greene and P. G. M. Wuts, Protective groups inOrganic Synthesis, 3^(rd) Edition, John Wiley & Sons, Inc. 1999). Then,coupling of the free amino group present on intermediate IX with avariety of synthetic amino acid in the presence of1-hydroxybenzotriazole (HOBt) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC) ledto derivative II in good to excellent yields. Finally, addition oftrimethysilyl bromide in dichloromethane (DCM) gave compound III in goodto excellent yields.

Scheme 3 presents the transformation of a diphenylmethyl derivative;(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (PL-100) into its fluorinated phosphate monoestersodium salt analog XI. This reaction sequence may be used to produce anyother similar compounds (compounds) made of unsubstituted (orsubstituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl and9-anthryl groups described in this invention.

Thus, the treatment of PL-100 with Selectfluor™ in acetonitrile gavederivative X in 38% yield. The introduction of the phosphate monoestergroup was performed as described previously in scheme 1 and 2. First,the diethyl phosphotriester intermediate was obtained in good yield upontreatment with diethyl chlorophosphate and sodium hydride in a mixtureof tetrahydrofuran and triethylphosphate. Secondly, addition oftrimethysilyl bromide in dichloromethane (DCM) gave the phosphatemonoester compound in good to excellent yields. The final product XI waseasily obtained upon treatment of the phosphate monoester with asolution of sodium hydroxide with good yields.

Scheme 4 illustrates a generic example for the transformation of aphosphotriester II into its fluorinated analog XIII in a two-stepreaction sequence. This generic example represents a second approach forthe synthesis of fluorinated compounds of this invention. In this case,the fluorine atom is added to the phosphotriester II instead of theprimary alcohol derivative of general formula I or, more specifically,PL-100 as shown on scheme 3. This alternate reaction sequence may beused to produce any other similar compounds made of unsubstituted (orsubstituted) diphenylmethyl, 1-naphthyl, 2-naphthyl, biphenyl and9-anthryl groups described in this invention.

Note:

a) R₂ and R₃ are as defined herein.

Briefly, treatment of derivative II with Selectfluor™ in acetonitrilegave derivative XII in good yields. Then, addition of trimethysilylbromide in dichloromethane (DCM) gave the phosphate monoester compoundXIII in good to excellent yields. If desired, the final product XIII maybe easily transformed into the phosphate monoester sodium salt analog asdescribed before in scheme 3.

Scheme 5 illustrates the synthesis of various ester compounds XVI inaccordance with the invention. The ester compounds are known to beeasily cleaved in vivo by esterase enzymes and, as a result, may releasethe active ingredient. In this scheme R₂ is set as a diphenylmethylgroup. However, this reaction sequence may be used to produce any othersimilar compounds made of unsubstituted (or substituted) diphenylmethyl,1-naphthyl, 2-naphthyl, biphenyl and 9-anthryl groups described in thisinvention.

Note:

a) R_(1A) represents the “residue” of the acid molecule that is linkedto the free primary alcohol group present on intermediate XV and is asdefined herein.

The compounds XVI are generally obtained in a three-step reactionsequence in high yields. Esterification of(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (VII) with a variety of acid in the presence of1-hydroxybenzotriazole (HOBt) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDAC) ledto the desired esters XIV in excellent yields. The acetyl ester wasobtained quantitatively using acetic anhydride in the presence ofN,N-dimethylaminopyridine (DMAP) in dichloromethane (DCM). Cleavage ofthe Boc protective group was achieved quantitatively upon treatment withtrifluoroacetic acid (TFA) in DCM. A second coupling with(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid is performed onthe primary amino group of intermediate XV with HOBt and EDAC to givethe desired compounds XVI in good to excellent yields. If necessary,catalytic hydrogenation of a benzyloxycarbonyl group is performed using10% palladium on carbon to give the final compound XVII.

As it may be appreciated by the person skilled in the art, the abovesynthetic schemes are not intended to be a comprehensive list of allmeans by which the compound described and claimed in this applicationmay be synthesized but only represent exemplification of synthesismethods among others. Further methods will be evident to those ofordinary skill in the art.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

As discussed above, the novel compounds may release the activeingredients that are excellent ligands for aspartyl proteases, forexample, HIV-1 protease. Accordingly, these compounds are, by releasingthe active ingredient, capable of targeting and inhibiting late stageevents in the replication, i.e. the processing of the viral polyproteinsby HIV encoded protease. Compounds according to this inventionadvantageously inhibit the ability of the HIV-1 virus to infectimmortalized human T cells over a period of days, as determined by anassay measuring the amount of extracellular p24 antigen; a specificmarker of viral replication (see, Meek et al., Nature, 343, pp. 90-92(1990)).

In addition to their use in the prophylaxis or treatment of HIV or HTLVinfection, the compounds according to this invention may also be used asinhibitory or interruptive agents for other viruses which use aspartylproteases, similar to HIV or HTLV aspartyl proteases, in their lifecycle. Such compounds inhibit the proteolytic processing of viralpolyprotein precursors by inhibiting aspartyl protease. Because aspartylprotease is essential for the production of mature virions, inhibitionof that processing effectively blocks the spread of virus by inhibitingthe production and reproduction of infectious virions, particularly fromacutely and chronically infected cells. The compounds of this inventionadvantageously inhibit aspartyl proteases, thus blocking the ability ofaspartyl proteases to catalyze the hydrolysis of peptide bonds.

The compounds of this invention may be employed in a conventional mannerfor the treatment or prevention of HIV, HTLV, and other viralinfections, which involve a spartyl proteases for their life(replication) cycle. Such methods of treatment, their dosage levels andrequirements may be selected by those of ordinary skill in the art fromavailable methods and techniques. For example, a compound of thisinvention may be combined with a pharmaceutically acceptable adjuvantfor administration to a virally infected patient in a pharmaceuticallyacceptable manner and in an amount effective to lessen the severity ofthe viral infection.

Alternatively, the compounds of this invention may be used in vaccinesand methods for protecting individuals against viral infection over anextended period of time. The compounds may be employed in such vaccineseither alone or together with other compounds of this invention in amanner consistent with the conventional utilization of proteaseinhibitors or protease inhibitors derivatives in vaccines. For example,a compound of this invention may be combined with pharmaceuticallyacceptable adjuvants, or delivery systems conventionally employed invaccines and administered in prophylactically effective amounts toprotect individuals over an extended period of time against viralinfections, such as HIV infection. As such, the novel compounds of thepresent invention (upon cleavage of a physiologically cleavable unit)may be administered as agents for treating or preventing viralinfections, including HIV infection, in a mammal.

The compounds of this invention may be administered to a healthy orHIV-infected patient (before or after the onset of AIDS symptoms) eitheras a single agent or in combination with other antiviral agents whichinterfere with the replication cycle of HIV. By administering thecompounds of this invention with other antiviral agents which targetdifferent events in the viral life cycle, the therapeutic effect ofthese compounds is potentiated. For instance, the co-administeredantiviral agent may be one which targets early events in the viral lifecycle, such as attachment to the cell receptor and cell entry, reversetranscription and viral DNA integration into cellular DNA. Antiviralagents targeting such early life cycle events include among otherspolysulfated polysaccharides, sT4 (soluble CD4) and other compoundswhich block binding of virus to CD4 receptors on CD4 bearingT-lymphocytes and other CD4(+) cells, or inhibit fusion of the viralenvelope with the cytoplasmic membrane, and didanosine (ddI),zalcitabine (ddC), stavudine (d4T), zidovudine (AZT) and lamivudine(3TC) which inhibit reverse transcription. For example another proteaseinhibitor may be used with compounds of the present invention. Otheranti-retroviral and antiviral drugs may also be co-administered with thecompounds of this invention to provide therapeutic treatment forsubstantially reducing or eliminating viral infectivity and the symptomsassociated therewith. Examples of other antiviral agents includeganciclovir, dideoxycytidine, trisodium phosphonoformate, eflornithine,ribavirin, acyclovir, alpha interferon and trimenotrexate. Additionally,other types of drugs may be used to potentiate the effect of thecompounds of this invention, such as viral uncoating inhibitors,inhibitors of Tat or Rev trans-activating proteins, antisense moleculesor inhibitors of the viral integrase. These compounds may also beco-administered with other inhibitors of HIV aspartyl protease.Furthermore, it may be found useful to administer compounds of thepresent invention with any other drug (other anti-viral compounds,antibiotics, pain killer, etc.,).

Combination therapies according to this invention exert a synergisticeffect in inhibiting HIV replication because each component agent of thecombination acts on a different site of HIV replication. The use of suchcombinations also advantageously reduces the dosage of a givenconventional anti-retroviral agent that would be required for a desiredtherapeutic or prophylactic effect as compared to when that agent isadministered as a monotherapy. These combinations may reduce oreliminate the side effects of conventional single anti-retroviral agenttherapies while not interfering with the anti-retroviral activity ofthose agents. These combinations reduce the potential of resistance tosingle agent therapies, while minimizing any associated toxicity. Thesecombinations may also increase the efficacy of the conventional agentwithout increasing the associated toxicity. Combination therapiesencompassed by the present invention include, for example, theadministration of a compound of this invention with AZT, 3TC, ddI, ddC,d4T or other reverse transcriptase inhibitors.

Alternatively, the compounds of this invention may also beco-administered with other HIV protease inhibitors such as Ro 31-8959(Saquinavir; Roche), L-735,524 (Indinavir; Merck), AG-1343 (Nelfinavir;Agouron), A-84538 (Ritonavir; Abbott), ABT-378/r (Lopinavir; Abbott),and VX-478 (Amprenavir; Glaxo) to increase the effect of therapy orprophylaxis against various viral mutants or members of other HIV quasispecies.

Administration of compounds of the present invention may be performed,for example, as single agents or in combination with retroviral reversetranscriptase inhibitors, or other HIV aspartyl protease inhibitors.Co-administration of the compounds of this invention with retroviralreverse transcriptase inhibitors or HIV aspartyl protease inhibitors mayexert a substantial synergistic effect, thereby preventing,substantially reducing, or completely eliminating viral infectivity andits associated symptoms.

The compounds of the present invention may be administered in such amanner or form which may allow cleavage of the R₁ unit to release aprotease inhibitor. The compounds of this invention may also beadministered, for example, in combination with immunomodulators (e.g.,bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF,methionine enkephalin, interferon alpha, diethyldithiocarbamate sodium,tumor necrosis factor, naltrexone and rEPO) antibiotics (e.g.,pentamidine isethionate) or vaccines to prevent or combat infection anddisease associated with HIV infection, such as AIDS and ARC.

When the compounds of this invention are administered in combinationtherapies with other agents, they may be administered sequentially orconcurrently to the patient. Alternatively, pharmaceutical orprophylactic compositions according to this invention may be comprisedof a combination of one or more compounds of this invention and anothertherapeutic or prophylactic agent.

Although this invention focuses on the use of the compounds disclosedherein for preventing and treating HIV infection, the compounds of thisinvention may also be used as inhibitory agents for other viruses thatdepend on similar aspartyl proteases for obligatory events in their lifecycle. These viruses include, but are not limited to, retrovirusescausing AIDS-like diseases such as simian imunuodeficiency viruses,HIV-2, HTLV-I and HTLV-II. In addition, the compounds of this inventionmay also be used to inhibit other aspartyl proteases and, in particular,other human aspartyl proteases including renin and aspartyl proteasesthat process endothelin precursors.

Pharmaceutical compositions of this invention comprise any of thecompounds of the present invention, and pharmaceutically acceptablesalts thereof, with any pharmaceutically acceptable carrier, adjuvant,or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of this inventioninclude, but are not limited to ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethyleneglycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The pharmaceutical compositions of this invention may be administeredorally, parenterally by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. It is thereforeunderstood herein that oral administration or administration byinjection are encompassed by the present invention. For example,compounds of the present invention, may, for example, be orallyadministered in an aqueous solution. The pharmaceutical compositions ofthis invention may contain any conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants or vehicles. The term “parenteral” asused herein includes subcutaneous, intracutaneous, intravenous,intramuscular, intra-articular, intrasynovial, intrasternal,intrathecal, intralesional and intracranial injection or infusiontechniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are amino acid, water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. Fatty acids, such as oleicacid and its glyceride derivatives are useful in the preparation ofinjectables, as are natural pharmaceutically-acceptable oils, such asolive oil or castor oil, especially in t heir polyoxyethylated versions.These oil solutions or suspensions may also contain a long-chain alcoholdiluent or dispersant, such as Ph. Helv or a similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, and aqueous suspension and solutions. Inthe case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also beadministered in the form of suppositories for rectal administration.These compositions may be prepared by mixing a compound of thisinvention with a suitable non-irritating excipient which is solid atroom temperature but liquid at the rectal temperature and therefore willmelt in the rectum to release the active components. Such materialsinclude, but are not limited to, cocoa butter, beeswax, and polyethyleneglycols.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For applicationtopically to the skin, the pharmaceutical composition should beformulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene or polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions may be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters waxcetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable neat formulation. Topically-transdermal patches arealso included in this invention.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

Dosage levels of between about 0.01 and about 25 mg/kg body weight perday, for example form between about 0.5 and about 25 mg/kg body weightper day of the active ingredient compound are useful in the preventionand treatment of viral infection, including HIV infection. Typically,the pharmaceutical compositions of this invention will be administeredfrom about 1 to about 5 times per day or alternatively, as a continuousinfusion. Such administration may be used as a chronic or acute therapy.The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thepatient treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). For example, such preparations may contain from about 20% toabout 80% active compound.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained. When thesymptoms have been alleviated to the desired level, treatment shouldcease. Patients may, however, require intermittent treatment on along-term basis, upon any recurrence of disease symptoms.

As the person skilled in the art will appreciate, lower or higher dosesthan those recited above may be desired. Specific dosage and treatmentregimen for any particular patient may depend upon a variety of factors,including the activity of the specific compound employed, the age, bodyweight, general health status, sex, diet, time of administration, rateof excretion, drug combination, the severity and course of theinfection, the patient's disposition to the infection and the judgmentof the treating physician.

In the description-herein, the following abbreviations are used:

ABBREVIATION MEANING

-   -   Ac Acetyl    -   AcOH Acetic acid    -   APCI Atmospheric pressure chemical ionization    -   AIDS Acquired Immunodeficiency Syndrome    -   AZT 3-Azido-3-deoxythymine (Zidovudine)    -   Boc Benzyloxycarbonyl    -   t-Butyl tert-Butyl    -   CAM Cerium ammonium molybdate    -   DCM Dichloromethane    -   DMAP N,N-dimethylaminopyridine    -   DMSO Dimethylsulfoxide    -   DMF Dimethylformamide    -   DNA Deoxyribonucleic acid    -   EDAC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide        hydrochloride    -   EtOAc Ethyl acetate    -   EtOH Ethyl alcohol    -   g Gram    -   h hour    -   HIV-1, -2 Human immunodeficiency virus type 1, type 2    -   HOBt 1-Hydroxybenzotriazole    -   HPLC High performance liquid chromatography        -   HTLV-I, -II Human T-cell lymphotropic virus type I, type II    -   IL-2 Interleukin-2    -   Kg Kilogram    -   L Liter    -   LC-MS Liquid chromatography-mass spectrometry    -   M Molar    -   MeOH Methyl alcohol    -   mg Milligram    -   mp Melting point    -   min Minute    -   Moc Methoxycarbonyl    -   mol Mole    -   mL Milliliter    -   mmol Millimole    -   nm Nanometer    -   nM Nanomolar    -   po Orally    -   rEPO Recombinant erythropoietin    -   TLC Thin layer chromatography    -   3TC 2′,3′-Dideoxy-3-thiacytidine    -   TFA Trifluoroacetic acid    -   THF Tetrahydrofuran

EXAMPLES

This section describes the synthesis of lysine based compounds able torelease an HIV aspartyl protease inhibitors as described herein. Theseexamples are for the purpose of illustration only and are not to beconstrued as limiting the scope of the invention in any way. Thissection presents the detailed synthesis of compounds no. 1 to 10 of thisinvention.

Materials and Methods

Analytical thin layer chromatography (TLC) was carried out with 0.25 mmsilica gel E. Merck 60 F₂₅₄ plates and eluted with the indicated solventsystems. Preparative chromatography was performed by flashchromatography, using silica gel 60 (EM Science) with the indicatedsolvent systems and positive air pressure to allow proper rate ofelution. Detection of the compounds was carried out by exposing elutedplates (analytical or preparative) to iodine, UV light and/or treatinganalytical plates with a 2% solution of p-anisaldehyde in ethanolcontaining 3% sulfuric acid and 1% acetic acid followed by heating.Alternatively, analytical plates may be treated with a 0.3% ninhydrinsolution in ethanol containing 3% acetic acid and/or a C AM solutionmade of 20 g (NH₄)₆Mo₇O₂₄ and 8.3 g Ce(SO₄)₂ polyhydrate in water (750mL) containing concentrated sulfuric acid (90 mL).

Preparative HPLC were performed on a Gilson apparatus equipped with aC18 column, a 215 liquid handler module and 25 mL/min capacity headpumps. The HPLC is operated with a Gilson UniPoint System Software.

Semi-Preparative HPLC Conditions for Purification of Test Compounds:

HPLC system: 2 Gilson #305-25 mL pumps, Gilson #215 liquid handler forinjection and collection and a Gilson #155 UV-Vis absorbance detector,all controlled from a Gilson Unipoint V 1.91 software

Column: Alltech (#96053) Hyperprep PEP, C-18, 100 Åα, 8 μm, 22×250 mm

Flow: 15 mL/min

Solvents: A: H₂O; B: CH₃CN

Gradient: 25% to 80% of B over 40 minDetector: absorbance; λ: 210 & 265 nm

The crude material dissolved in acetonitrile to a concentration ofaround 50 to 80 mg/2 mL were injected in each run. Fractions werecollected in amounts of 9 mL pertaining absorbance was detected at theUV detector.

Unless otherwise indicated, all starting materials were purchased from acommercial source such as Aldrich Co. or Sigma Co.

Melting points (mp) were determined on a Büch 530 melting pointapparatus in capillary tubes and were uncorrected.

Mass spectra were recorded on a Hewlett Packard LC/MSD 1100 system usingAPCI or electrospray sources either in negative mode or positive mode.

Nuclear magnetic resonance (NMR) spectra were recorded on a BrukerAMX-II-500 equipped with a reversed or QNP probe. Samples were dissolvedin deuterochloroform (CDCl₃), deuteroacetone (acetone-d₆),deuteromethanol (CD₃OD) or deuterodimethylsulfoxide (DMSO-d₆) for dataacquisition using tetramethylsilane as internal standard. Chemicalshifts (*) are expressed in parts per million (ppm), the couplingconstants (J) are expressed in hertz (Hz) whereas multiplicities aredenoted as s for singlet, d for doublet, 2d for two doublets, dd fordoublet of doublets, t for triplet, q for quartet, quint for quintet, mfor multiplet, and br s for broad singlet.

DETAILED DESCRIPTION OF THE INVENTION Examples Specific Examples for thePreparation of Derivatives of General Formula I

The following compounds were prepared from L-lysine derivatives usingthe procedures summarized in schemes 1, 1A, 2, 3, 4 and 5 of thisinvention.

Example 1 Preparation of(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (PL-461)

The preparation of the title compound is based on schemes 1 and 2 ofthis invention.

Step A. Preparation of (3S)-3-isobutylamino-azepan-2-one (IV)

L-α-amino-,-caprolactam (22.0 g) was dissolved in cold dichloroethane(DCM, 200 mL) isobutyraldehyde (12.6 g) was added slowly and stirreduntil the heat evolved was dissipated (water forms at the surface). Thecold solution was added to 46.5 g of powdered NaBH(OAc)₃ in DCM (0.5 L).AcOH (70 mL) was added to the solution. The slightly turbid mixture wasstirred at 20° C. for 4 h. A 500 mL solution of 2M NaOH was added slowlyto the turbid mixture and the pH adjust to 11 using a concentrated NaOHsolution, and then the mixture stirred for a further 20 min. Afterextraction, the DCM layer was dried with MgSO₄, filtered and evaporated.The oil thus obtained crystallizes slowly on standing (27.8 g, 85%) andwas used without further purification in the next step.

¹H NMR (CDCl₃): δ 0.93 (d, J=6.5, 3H), 0.97 (d, J=6.5, 3H), 1.39 (t,J=9.8, 1H), 1.47 (m, 1H), 1.78-1.65 (m, 2H), 2.00-1.93 (m, 2H), 2.32-2.2(m, 2H), 2.38 (t, J=9.7, 1H), 3.16 (m, 3H), 6.62 (s, 1H(NH)). mp 52-54°C. (hexanes).

A small sample was converted to the S-methyl benzyl urea by adding thesolid to a solution of S-methyl benzyl isocyanate in MeCN. NMR gives 98%ee

Step B. Preparation ofNα-isobutyl-Nα-(4-acetamidobenzenesulfonyl)-L-α-amino-,-caprolactam (V)

Nα-isobutyl-L-α-amino-,-caprolactam (IV) (4.1 g free base) was dissolvedin DCM (200 mL) and treated with 4.0 g triethylamine, followed by4-acetamidobenzenesulfonyl chloride (5.2 g). A 0.1 g portion ofdimethylaminopyridine was added and the mixture was stirred 5 h. Theresulting thick slurry was poured into 500 mL 0.5 M HCl and shakenvigorously. The solid in the biphasic solution was filtered out andwashed with cold acetone to give 7.3 g (87%) of clean product.

¹H NMR (DMSO-d₆): * 0.93 (d, J=6.0, 3H), 0.96 (d, J=6.0, 3H), 1.39 (t,J=12.0, 1H), 1.85-1.65 (m, 3H), 2.08-2.18 (m and s, 6H), 2.90-2.97 (m,1H), 3.00-3.06 (m, 2H), 3.35 (dd, J=14.2, 8.5, 1H), 4.65 (d, J=8.7, 1H),6.3 (s, 1H), 7.42 (d, J=8.8, 2H), 7.6 (d, J=8.8, 2H). mp 230-233° C.(EtOH).

Step C. Preparation of(3S)-3-{[4-(acetyl-tert-butoxycarbonyl-amino)-benzenesulfonyl]-isobutyl-amino}-2-oxo-azepane-1-carboxylicacid tert-butyl ester (Boc activation) (VI)

4.2 g ofNα-isobutyl-Nα-(4-acetamidobenzenesulfonyl)-L-α-amino-,-caprolactam (V)was suspended in 30 mL MeCN and briefly sonicated to break up any largechunks. To this white suspension was added 6.7 g (3 eq.) ofdi-tert-butyl pyrocarbonate in 10 mL MeCN. The suspension was stirredwith a magnetic bar and a 120 mg portion of DMAP was added. The solutionbecomes a clear light yellow after a few minutes. TLC (EtOAc) reveals 1product Rf 0.9 (starting material Rf at 0.4). The solution is poured indistilled water 20 mL and extracted with ether, dried with Na₂SO₄ andevaporated yielding 6.90 g. A sample was recrystallized from hexanes.

¹H NMR (DMSO-d₆): * 0.68 (d, J=6.0, 3H), 0.85 (d, J=6.0, 3H), 1.39 (s,10H), 1.47 (s, 9H), 1.85-1.65 (m, 3H), 2.15 (s, 3H), 2.80 (q, J=4, 1H),3.10-3.36 (m, 2H), 4.01 (d, J=8.0, 1H), 4.85 (d, J=8.7, 1H), 7.32 (d,J=8.8, 2H), 7.87 (d, J=8.8, 2H). mp 123-124° C.

Step D. Preparation of(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(VII-deprotected) (Reductive Ring Opening and Deprotection)

A 3.0 g portion of(3S)-3-{[4-(acetyl-tert-butoxycarbonyl-amino)-benzenesulfonyl]-isobutyl-amino}-2-oxo-azepane-1-carboxylicacid tert-butyl ester (VI, step C) is dissolved in 40 mL EtOH followedby 750 mg NaBH₄. Brief heating with a heat gun gives a clear solution.TLC reveals one streaky spot after 20 min (EtOAc). The solution isconcentrated to a paste, poured in 40 mL 1N NaOH and extracted withethyl acetate, the organic phase dried with NaSO₄ and evaporated to give2.8 g of product intermediate (VII);(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (VII).

The above product intermediate is dissolved in 5 mL EtOH and 5 mL 12 NHCl is added. Vigorous gas evolution is observed for a few minutes.After 2 h the solution is evaporated and rendered basic withconcentrated KOH and extracted with EtOAc yielding 1.75 g of a whitepowder.

¹H NMR (DMSO-d₆): * 0.82 (m, 6H), 0.97-1.12 (m, 2H), 1.15-1.30 (m, 3H),1.57 (m, 1H), 1.84 (m, 1H), 2.40 (t, J=7.8, 2H), 2.75 (m, 1H), 2.85 (m,1H), 3.21 (m, 1H), 3.44 (d, J=6.4, 2H), 5.92 (br s, 2H), 6.59 (d, J=8.0,2H), 7.39 (d, J=8.0, 2H).

Step E. Preparation (2S)-2-methoxycarbonylamino-3,3-diphenyl-propionicacid

To a solution of L-diphenylalanine (241 mg, 1.0 mmol) Peptech Corp.) in5 mL 1N NaOH and 0.5 mL saturated Na₂CO₃ (resulting solution at pH 10)was added methoxycarbonyloxysuccinimide (carbonic acid2,5-dioxo-pyrrolidin-1-yl ester methyl ester) (180 mg, 1.1 mmol)dissolved in 5 mL. Afterwards, the reaction mixture was stirred at roomtemperature for 2 h. The alkaline solution was extracted once with ether(10 mL) and the aqueous phase was acidified with 1N HCl. This wasextracted twice with 20 mL EtOAc, and the combined organic phases werewashed with 50 mL 1N HCl. The organic phase was dried over Na₂SO₄,filtered and evaporated to an oil, which solidifies to yields 250 mg(83%) of the desired material. This derivative was used as such in thenext step.

Step F. Preparation of(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (PL-100)

The title compound was prepared from(1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide(VII-deprotected) (step D) and(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (step E) usingthe coupling procedure with HOBt and EDAC described in example 3 (stepD). The final product was obtained in 67% yield (121 mg).

LC-MS: 625.3 (M+H)⁺, 95% pure

¹H NMR (CD₃OD): δ 0.71-0.85 (m, 2H), 0.88 (d, J=6.3, 5H), 0.91-0.96 (m,2H), 1.29-1.34 (m, 1H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68(m, 1H), 2.81-2.85 (m, 2H), 2.94-3.05 (m, 2H), 3.38-3.40 (t, J=5.0, 1H),3.50-3.51 (m, 1H), 3.52 (s, 3H), 4.28 (d, J=11.0 1H), 4.87 (d, J=11.0,1H), 6.69 (d, J=8.0, 2H), 7.15-718 (m, 2H), 7.20-7.31 (m, 6H), 7.33 (d,J=7.9, 2H), 7.47 (d, J=7.5, 1H).

¹³C NMR (CD₃OD): δ 20.0, 20.1, 23.3, 25.4, 28.1, 28.5, 28.9, 38.1, 40.0,51.2, 51.6, 53.1, 57.2, 57.4, 59.5, 61.9, 62.4, 112.6, 125.7, 126.2,126.3, 127.9, 128.1, 128.15, 128.2, 128.4, 128.7, 141.3, 141.9, 152.4,155.9, 169.9, 172.5.

Step G. Preparation of(1S,5S)-{1-[5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(diethoxy-phosphoryloxy)-hexylcarbamoyl]-2,2-diphenyl-ethyl}-carbamicacid methyl ester

The PL-100 compound (product of step F, 203 mg, 0.325 mmol) wasdissolved in dry tetrahydrofuran (3 mL) and 0.2 mL triethylphosphateunder N₂ atmosphere. The mixture was stirred at this temperature for 15min, followed by the addition of diethyl chlorophosphate (0.061 mL,0.423 mmol). Sodium hydride (60% in mineral oil) (17 mg, 0.423 mmol) wasadded at 0° C. The solution was stirred for 1 h at 0° C. and 12 h atroom temperature. 20 mL of Amberlite XAD-2 was added to the solution andthe beads were thoroughly mixed with the solvent. To the mixture wasadded ice water 2 mL, and the THF evaporated off. The beads were thenwashed with distilled water 6 times 100 mL then extracted three timeswith ethyl acetate (30 mL). The combined phase was evaporated and theresidue was dried under high vacuum. The crude product was purified byflash chromatography using ethyl acetate/hexane (8/2), then EtOAc 100%as eluent. The yield of this reaction is 152 mg 61%.

LC-MS: 761.2 (M+H)⁺, 90% pure

¹H NMR (CD₃OD): δ 0.68-0.75 (m, 1H), 0.75-0.84 (m, 1H), 0.84-1.10 (m,9H), 1.21-1.50 (m, 8H), 1.88 (m, 1H), 2.58-2.71 (m, 1H), 2.80-2.89 (m,1H), 2.89-3.08 (m, 2H), 3.49-3.60 (s, 3H), 3.65-3.74 (m, 1H), 3.85-3.95(m, 1H), 3.97-4.02 (m, 1H), 4.07-4.21 (m, 4H), 4.29 (d, J=10.8, 1H),6.71 (d, J=8.0, 2H), 7.10-7.20 (m, 2H), 7.20-7.32 (m, 5H), 7.32-7.45 (m,3H), 7.50 (d, J=7.5, 2H), 7.86 (br s, 1H).

³¹P NMR (CD₃OD): δ 1.62

Step H. Preparation of(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (PL-461)

The product of step G prepared above (152 mg) was dissolved in anhydrousdichloromethane (3.0 mL). Trimethylsilyl bromide (0.5 mL) was added at0° C. The mixture was stirred during 1 h at this temperature andovernight at room temperature. The solvent was evaporated and 0.2 mLwater was added to the residue. 3 mL EtOH was added mixed andevaporated. This step was repeated three times and the residue dried invacuo. Yields 98 mg 70% of the title derivatives of this first example.

LC-MS: 705.2 (M+H)⁺, 95% pure

¹H NMR (CD₃OD): δ 0.65-0.73 (m, 1H), 0.75-0.83 (m, 1H), 0.89 (d, J=5.6,8H), 1.27-1.38, (m, 1H), 1.42-4.55 (m, 1H), 1.82-1.94 (m, 1H), 2.57-2.68(m, 1H), 2.78-2.90 (m, 1H), 2.91-3.09 (m, 2H), 3.54 (s, 3H), 3.60-3.72(m, 1H), 3.87-4.05 (m, 1H), 4.00 (m, 1H), 4.29 (d, J=11.3, 1H), 4.90 (d,J=11.4, 1H), 6.73 (d, J=8.0, 2H), 7.13-7.22 (m, 2H), 7.22-7.33 (m, 6H),7.33-7.45 (m, 2H), 7.51 (d, J=7.5, 2H). ³¹P NMR (CD₃OD): δ 2.80

Example 2 Preparation of(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester sodium salt (PL-462)

70.7 mg of the final product of example 1 is added to 1 mL 0.1 N NaOHand diluted with 1 mL of distilled water. The Solution is then frozenand lyophilized. Yields 67.2 mg (92%) of the desired material with 95%purity.

¹H NMR (CD₃OD): δ 0.72-0.83 (m, 1H), 0.90 (d, J=5.8, 9H), 1.26-1.38 (m,1H), 1.53-1.65 (m, 1H), 1.88-2.00 (m, 1H), 2.60-2.70 (m, 1H), 2.79-2.89(m, 1H), 2.98-3.00 (m, 1H), 3.00-3.08 (m, 1H), 3.54 (s, 3H), 3.58-3.71(m, 1H), 3.72-3.83 (m, 1H), 3.84-3.95 (m, 1H), 4.28 (d, J=11.1, 1H),4.91 (d, J=11.0, 1H), 6.70 (d, J=7.6, 2H), 7.12-7.22 (m, 2H), 7.22-7.32(m, 6H), 7.33-7.40 (m, 2H), 7.50 (d, J=7.7, 2H). ³¹P NMR (CD₃OD): δ 3.13

Example 3 Preparation of(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-naphthalen-2-yl-ethyl)-carbamicacid methyl ester (PL-507)

The preparation of the title compound is based on scheme 2 of thisinvention.

Step A. Preparation of(1S)-(4-{[5-tert-butoxycarbonylamino-1-(diethoxyphosphoryloxymethyl)-pentyl]-isobutyl-sulfamoyl}-phenyl)-carbamicacid tert-butyl ester (VIII)

2.00 g (3.7 mmol)(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (VII) (example 1, step D) is dissolved in 0.63 mLtriethylphosphate and 10 mL THF at 0° C. under inert argon atmosphere.0.63 mL (4.44 mmol) diethylchlorophosphate is added and then 0.25 g (6.2mmol), NaH 60% in oil is added in portionwise. The mixture is allowed towarm to room temperature and left to stir for 2 h (LC-MS showedcompletion after 1 h). To the solution is added 20 mL of Amberlite XAD-2resin and the slurry thoroughly mixed and added to 200 mL ice water.After stirring for 15 min. the resin suspension is filtered and theresin washed several times with distilled water (500 mL). The desiredproduct is desorbed from the resin with acetone (5×50 mL), EtOAc (5×50mL), the organic phase is then dried over Na₂SO₄. After evaporation ofthe solvent 2.66 g (89%) of clear oil is obtained. The crude productcontains a fraction with two diethyl phosphates and is used as is in thenext step.

¹H NMR (CD₃OD): δ 0.91 (d, J=6.3, 6H), 1.11-1.21 (m, 2H), 1.33 (t,J=6.9, 10H), 1.43 (s, 9H), 1.53 (s, 10H), 1.90-1.97 (m, 1H), 2.88-2.96(m, 3H), 2.96-3.04 (m, 1H), 3.81-3.90 (m, 1H), 3.91-3.99 (m, 1H),4.01-4.14 (m, 4H), 7.61 (d, J=8.3, 2H), 7.72 (d, J=8.4, 2H). ³¹P NMR(CD₃OD): δ 1.59

Step B. Preparation of (2S)-phosphoric acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester diethylester (IX)

The crude product obtained in the previous step (VIII, 2.66 g) isdissolved in 12 mL EtOH. 4 mL of HCl is added and heated briefly to 70°C. then left at room temperature for 3 h. The solvent is evacuated andthe residue triturated with 50 mL ether. The thick residue is thendissolved in 3 mL ice water and the pH adjusted to 12 with 50% NaOH. Thethick slurry obtained is extracted with EtOAc (3×50 mL) and the organicphase dried over Na₂SO₄. After filtration of the drying agent theorganic phase is evacuated to yield 1.84 g (98%) of the desired product(IX).

LC-MS: 480.2 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.91 (s, 6H), 1.11-1.26 (m, 3H), 1.28-1.43 (m, 8H),1.45-1.51 (m, 1H), 1.52-1.61 (m, 1H), 1.89-1.96 (m, 1H), 2.56 (t, J=6.7,2H), 2.85-2.91 (m, 1H), 2.98-3.11 (m, 1H), 3.79-3.99 (m, 1H), 3.94 (d,J=5.3, 1H), 4.09-4.11 (m, 4H), 6.69 (d, J=7.9, 2H), 7.50 (d, J=7.9, 2H).

³¹P NMR (CD₃OD): δ 1.61

Step C. Preparation of(2S)-2-methoxycarbonylamino-3-naphthalen-2-yl-propionic acid (orL-Moc-2-naphthylalanine)

To a solution of L-2-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in5 mL 1N NaOH and 0.5 mL saturated Na₂CO₃ (resulting solution at pH 10)was added methoxycarbonyloxysuccinimide (187 mg, 1.1 mmol) dissolved in5 mL. Afterwards, the reaction mixture was stirred at room temperaturefor 2 h. The alkaline solution was extracted once with ether (10 mL) andthe aqueous phase was acidified with 1N HCl. This was extracted twicewith 20 mL EtOAc, and the combined organic phases were washed with 50 mL1N HCl. The organic phase was dried over Na₂SO₄, filtered and evaporatedto an oil, which solidifies to yields 200 mg (73%) of the desiredmaterial. This intermediate (referred as the N-substituted amino acid)was used without further purification in the next step.

Step D. Preparation of(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2-naphthalen-2-yl-ethyl)-carbamicacid methyl ester (PL-507)

100 mg L-Moc-2-naphthylalanine (step C) was activated with 100 mg EDACand 57 mg HOBt in 1.5 mL DMF for 30 minutes. Then, 100 mg of phosphoricacid 6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl esterdiethyl ester (step B) was added and left to stir at room temperaturefor 1 h. 40 mL of 1M K₂CO₃ was added to the DMF solution and left for 10min. 50 mL of EtOAc was then added and the mixture was then agitatedvigorously. Separation of the EtOAc phase was effected, followed byextraction with 5% citric acid (50 mL) once, then water (50 mL) 3 timesand finally brine. The organic phase was the separated and evaporated.The residue was taken up in 50 mL DCM and re-evaporated. The residue wasagain taken up in 50 mL DCM and 0.5 mL of TMSBr was added. The solutionwas left overnight (16 h). The DCM was evacuated and a solution of icecold MeOH:Water 1:1 was added, stirred briefly and evacuated. Theresidue was triturated with ether then dissolved in 1N NaOH. The clearsolution was extracted with ether and the aqueous phase acidified with6N HCl. The white precipitated was then collected by filtration anddried in vacuo overnight. Yields 88 mg of the title compound.

LC-MS: 679.8 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.89-0.98 (m, 8H), 1.15 (m, 2H), 1.35 (m, 1H), 1.45(m, 1H), 1.88 (m, 1H), 2.84 (m, 2H), 2.98 (m, 1H), 3.01 (m, 2H), 3.24(m, 1H), 3.56 (s, 3H), 3.60 (m, 1H), 3.81 (m, 1H), 3.99 (m, 1H), 4.39(t, J=6.8, 1H), 6.91 (d, J=8.0, 2H), 7.34 (d, J=8.0, 1H), 7.45 (m, 2H),7.58 (d, J=8.0, 2H), 7.66 (s, 1H), 7.70-7.82 (m, 3H). ³¹P NMR (CD₃OD): δ2.56

Example 4 Preparation of (2S,2S) phosphoric acidmono-(2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-{2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionylamino}-hexyl)ester (PL-498) Step A. Preparation of(2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid

To a solution of L-1-naphthylalanine (215 mg, 1 mmol) (Peptech Corp.) in5 mL 1N NaOH and 0.5 mL saturated Na₂CO₃ (resulting solution at pH 10)was added morpholine-4-carbonyl chloride (150 mg, 1.0 mmol) dissolved in5 mL. Afterwards, the reaction mixture was stirred at room temperaturefor 2 h. The alkaline solution was extracted once with ether (10 mL) andthe aqueous phase was acidified with 1N HCl. This was extracted twicewith 20 mL EtOAc, and the combined organic phases were washed with 50 mL1N HCl. The organic phase was dried over Na₂SO₄, filtered and evaporatedto an oil, which solidifies to yields 125 mg (38%) of the desiredmaterial. This compound was used as such in the next step.

Step B. Preparation of (2S,2S) Phosphoric acidmono-(2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-{2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionylamino}-hexyl)ester (PL-498)

This compound was made as for the preparation of the product of example3 (step D) with 100 mg of(2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid(step A of this example). The resulting precipitated residue was furtherpurified by reverse phase preparative HPLC. Yields 41 mg of the finalcompound.

LC-MS: 734.8 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.83-0.98 (m, 8H), 1.00-1.25 (m, 4H), 1.45-1.52 (m,1H), 1.52-1.66 (m, 1H), 1.88-1.99 (m, 1H), 2.77-2.92 (m, 2H), 2.98-3.16(m, 3H), 3.40-3.49 (m, 1H), 3.50-3.56 (m, 6H), 3.67-3.69 (m, 1H),3.81-3.89 (m, 1H), 3.99-4.05 (m, 1H), 4.59 (t, J=6.0, 1H), 6.75 (d,J=8.0, 2H), 7.30-7.60 (m, 7H), 7.75 (d, J=8.0, 1H), 7.90 (d, J=7.8, 1H),8.23 (d, J=7.8 2H).

³¹P NMR (CD₃OD): δ 2.71

Example 5 Preparation of (2S,2S)-phosphoric acidmono-{6-(2-acetylamino-3,3-diphenyl-propionylamino)-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl}ester(PL-504) Step A. Preparation (2S)-2-acetylamino-3,3-diphenyl-propionicacid

To a solution of L-diphenylalanine (100 mg, 0.4 mmol) (Peptech Corp.) in5 mL 1N NaOH and 0.5 mL saturated Na₂CO₃ (resulting solution at pH 10)was added acetyl chloride (0.5 mmol) dissolved in 5 mL. Afterwards, thereaction mixture was stirred at room temperature for 2 h. The alkalinesolution was extracted once with ether (10 mL) and the aqueous phase wasacidified with 1N HCl. This was extracted twice with 20 mL EtOAc, andthe combined organic phases were washed with 50 mL 1N HCl. The organicphase was dried over Na₂SO₄, filtered and evaporated to an oil, whichsolidifies to yields 70 mg (60%) of the desired material. This crudeintermediate was used as such in the next step.

Step B. Preparation of (2S,2S)-phosphoric acidmono-{6-(2-acetylamino-3,3-diphenyl-propionylamino)-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl}ester(PL-504)

This compound was made as for the preparation of the product of example3 (step D) with 100 mg of (2S)-2-acetylamino-3,3-diphenyl-propionic acid(this example step A). The final product was obtained in 30% yield (30mg).

LC-MS: 689.3 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.77-1.04 (m, 9H), 1.10-1.17 (m, 1H), 1.23-1.49 (m,1H), 1.46-1.57 (m, 1H), 1.78 (s, 3H), 1.88-1.99 (m, 1H), 2.80-2.92 (m,2H), 2.92-3.08 (m, 2H), 3.63-3.75 (m, 1H), 3.79-3.95 (m, 1H), 4.00 (m,1H), 4.34 (d, J=11.3, 1H), 5.19-5.28 (m, 1H), 6.77-6.85 (m, 2H),7.10-7.20 (m, 2H), 7.27-7.33 (m, 6H), 7.32-7.41 (m, 2H), 7.49-7.62 (m,2H). ³¹P NMR (CD₃OD): δ 2.70

Example 6 Preparation of(1S,5S)-(1-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (PL-515)

First methodology: The preparation of the title compound is based onscheme 3 of this invention.

Step A. Preparation of(1-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-hydroxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (X) (PL-337)

The product of example 1, step F (0.624 g, 1 mmol) is dissolved in 5 mLMeCN at 24° C. SelectFluor 0.35 g (1 mmol) is added in one portion andstirred for 1 h. 1 mL of water is added and the solution was injecteddirectly into a preparative reverse-phase HPLC. The product wascollected and lyophilized to give 250 mg (38%) yield of a white solid.

LC-MS: 643.3 (M+H)⁺, 99% pure.

¹H NMR (MeOD): δ 0.71-0.85 (m 2H), 0.88 (d, J=6.3, 6H), 0.91-0.96 (m,2H), 1.21-1.29 (m, 1H), 1.41-1.52 (m, 1H) 1.82-1.92 (m, 1H), 2.61-2.68(m, 1H), 2.81-2.85 (m, 2H), 2.94-3.05 (m, 2H), 3.38-3.40 (t, J=5, 1H),3.49-3.52 (m, 5H), 4.28 (d, J=10, 1H), 4.87 (d, J=10, 1H) 6.90 (t,J=8.3, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H).

Step B. Preparation of(1S,5S)-{1-[5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-(diethoxy-phosphoryloxy)-hexylcarbamoyl]-2,2-diphenyl-ethyl}-carbamicacid methyl ester

The product of step A was phosphorylated with chlorodiethylphosphatefollowing the procedure described in example 1, step G. Yields 157 mg,68%.

LC-MS: 779.3 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.82 (m, 1H), 0.92 (d, J=6.2, 8H), 0.96 (m, 3H), 1.36(d, J=3.7, 6H), 1.90 (m, 1H), 2.69 (m, 1H), 2.89 (m, 1H), 2.98 (m, 2H),3.56 (s, 3H), 3.74 (m, 1H), 3.93 (m, 1H), 4.03 (m, 1H), 4.12 (q, J=7.5and 14.8, 4H), 4.32 (d, J=11.4, 1H), 4.92 (d, J=11.4, 1H), 6.90 (t,J=8.3, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.33 (m, 3H), 7.39 (m, 4H).

³¹P NMR (CD₃OD): δ 1.65

Step C. Preparation of(1S,5S)-(1-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (XI) (PL-515)

Deprotection was effected using the procedure described in example 1,step G. Yields 101 mg.

LC-MS: 723.2 (M+H)⁺, 95% pure.

¹H NMR (CD₃OD): δ 0.65-0.77 (m, 1H), 0.77-0.85 (m, 1H), 0.85-1.05 (m,9H), 1.25-1.39 (m, 1H), 1.40-1.52 (m, 1H), 1.82-1.98 (m, 1H), 2.58-2.72(m, 1H), 2.82-2.92 (m, 1H), 2.92-3.05 (m, 2H), 3.54 (s, 3H), 3.64-3.75(m, 1H), 3.80-3.92 (m, 1H), 3.91-4.04 (m, 1H), 4.29 (d, J=11.4, 1H),7.19 (t, J=6.6, 1H), 7.13-7.21 (m, 2H), 7.22-7.33 (m, 6H), 7.34-7.38 (m,2H), 7.39-7.48 (m, 2H).

³¹P NMR (CD₃OD): δ 2.74

Second methodology: The preparation of the title compound is based onscheme 4 of this invention.

Step A. Preparation(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (PL-461)

(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid ((example 1,step E) 0.9 g, 3 mmol) was activated in DMF (5 mL) with EDAC (1.7 g, 9mmol) and HOBt (1.2 g, 9 mmol). To the solution was added 1.17 g of(2S)-phosphoric acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester diethylester (IX) (example 3, step B) and the mixture stirred for 3 h. 20 g ofAmberlite XAD-2 resin was then added and the beads were left to soak for10 min. The resin was transferred into a glass filter and washedthoroughly with distilled water (400 mL) and 200 mL of 1M NaHCO₃. Thebeads were then washed with 4×50 ml portions of MeOH then EtOAc 200 mL.The organic phase was evaporated. The residue was adsorbed onto silicagel and passed through a short silica gel column (EtOAc) to yield 2.4 g(83%) of white solid after evaporation.

NMR identical as in example 1, step H.

Step B. Preparation(1S,5S)-{1-[5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-(diethoxy-phosphoryloxy)-hexylcarbamoyl]-2,2-diphenyl-ethyl}-carbamicacid methyl ester (XII)

The product of step A above,(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxyhexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamic acid methyl ester (0.555 g,0.73 mmol) was dissolved in 5 mL MeCN. Selectfluor (0.26 g, 0.7 mmol)was added and the mixture stirred for 30 min. The mixture was purifiedby reverse phase preparative HPLC and lyophilized to yield 278 mg (48%yield) white solid.

¹H NMR identical as previous entry, see first methodology above.

Step C. Preparation(1S,5S)-(1-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexylcarbamoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester (XIII, in this Specific Case is Compound XI) (PL-515)

The procedure make this derivative was as described in the deprotectionstep for the methodology above. Yields 139 mg 70% after reverse phaseHPLC.

¹H NMR identical as previous entry, see first methodology above.

Example 7 Preparation of (2S,2S)-acetic acid2-[(4-amino-benzenesulfonyl)-isobutyl—amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (PL-521)

The preparation of the title derivative is based on scheme 5 of thisinvention.

Step A. Preparation of (2S)-acetic acid6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexylester (XIV, R_(1A)═CH₃)

To a stirred solution of(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (intermediate product (VII) of example 1, step D,97 mg, 0.18 mmol) in anhydrous CH₂Cl₂ (3 mL) was addedN,N-dimethylaminopyridine (22 mg, 0.18 mmol) and acetic anhydride (0.014mL, 0.18 mmol). The mixture was stirred at room temperature for 1 hour.The solvent was evaporated. Ethyl acetate (50 mL) was added and theorganic layer was washed with water (30 mL), then dried with Na₂SO₄ andconcentrated. The residue was purified by flash chromatography elutingwith ethyl acetate. The yield obtained was quantitative (100 mg).

LC-MS: 586.2 (M+H)⁺, 95% pure

Step B. Preparation of (2S)-acetic acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (XV,R_(1A)═CH₃)

This derivative was prepared from (2S)-acetic acid6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexylester as described in example 15, step B. The yellow solid (66 mg) wasused for the next reaction without purification.

LC-MS: 386.2 (M+H)⁺, 95% pure

Step C. Preparation of (2S,2S)-acetic acid2-[(4-amino-benzenesulfonyl-)isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (XVI, R_(1A)═CH₃) (PL-521)

This derivative was prepared from (2S)-acetic acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester(product of step B) as described in example 15, step B. The finalproduct was purified by flash chromatography with a mixture of eluentshexane/ethyl acetate (2/8). A yellow solid was obtained in 70% yield (70mg).

LC-MS: 667.3 (M+H)⁺, 95% pure

¹H NMR (acetone-d₆): δ 0.85-0.97 (m, 12H), 1.21-1.41 (m, 2H), 1.88-2.00(s, 3H), 2.59-2.69 (m, 1H), 2.83-2.90 (m, 1H), 2.90-3.01 (m, 1H),3.01-3.10 (br s, 1H), 3.45-3.60 (s, 3H), 3.70-3.80 (m, 1H), 3.93-4.00(m, 1H), 4.00-4.11 (m, 1H), 4.38-4.45 (d, J=11.0, 1H), 4.89-4.98 (t,J=10.0, 1H), 5.43-5.58 (br s, 1H), 6.28-6.48 (d, J=8.9, 1H), 6.72-6.83(d, J=8.0, 2H), 6.85-6.93 (br s, 1H), 7.12-7.22 (t, J=7.4, 1H),7.21-7.31 (d, J=7.0, 4H), 7.31-7.45 (m, 5H), 7.48-7.57 (d, J=8.0, 2H).

Example 8 Preparation of (2S,2S)-nicotinic acid2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (PL-520) Step A. Preparation of (2S)-nicotinic acid6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexylester (XIV, R_(1A)=3-pyridyl)

(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (intermediate product (yl) of example 1, step D,130 mg, 0.24 mmol) was dissolved in anhydrous DMF (1 mL) and treatedwith 0.066 mL (0.48 mmol) of triethylamine followed by EDC (120 mg, 0.65mmol), HOBt (88 mg, 0.65 mmol) and nicotinic acid (27 mg, 0.22 mmol).The mixture was stirred overnight at room temperature. The product wasextracted with ethyl acetate (40 mL) and water (40 mL). The organicphase was separated and dried with Na₂SO₄, then evaporated to give 200mg of crude product. This compound was purified by flash chromatographywith ethyl acetate as the eluent. A clear oil was obtained in 100% yield(150 mg).

LC-MS: 649.3 (M+H)⁺, 95% pure

¹H NMR (acetone-d₆): δ 0.90-1.14 (d, J=5.9, 6H), 1.31-1.42 (m, 2H), 1.48(s, 9H), 1.51-1.55 (m, 2H), 1.59 (s, 9H), 1.62-1.69 (m, 1H), 1.72-1.83(m, 1H), 3.00-3.11 (m, 2H), 3.11-3.17 (m, 1H), 3.19-3.27 (m, 1H),4.15-4.24 (m, 1H), 4.35-4.44 (t, J=9.1, 1H), 4.50-4.58 (dd, J=4.4 and11.5, 1H), 5.89-5.99 (br s, 1H), 7.53-7.60 (m, 1H), 7.70-7.77 (d, J=8.2,2H), 7.80-7.87 (d, J=8.2, 2H), 8.24-8.31 (d, J=7.3, 1H), 8.75-8.82 (m,1H), 8.82-8.88 (m, 1H), 9.12-9.18 (br s, 1H).

Step B. Preparation of (2S)-nicotinic acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (XV,R_(1A)=3-pyridyl)

The product of step A, (2S)-nicotinic acid6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexylester (150 mg, 0.23 mmol), was dissolved in CH₂Cl₂ (5 mL) andtrifluoroacetic acid (1 mL) was added. The mixture was stirred during 2hours at room temperature. The solvent was evaporated and the residuewas extracted with ethyl acetate (40 mL) and NaOH 1M (40 mL) (pH=10).The organic portion was separated, dried with Na₂SO₄ and evaporated. Theresidue (100 mg) was used for the next reaction without furtherpurification. The yield was quantitative.

LC-MS: 449.2 (M+H)⁺, 95% pure

Step C. Preparation of (2S,2S)-nicotinic acid2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (PL-520)

The product of step B, (2S)-nicotinic acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (100mg, 0.22 mmol) was dissolved in anhydrous. DMF (2 mL) and treated with0.062 mL (0.45 mmol) of triethylamine followed by EDC (100 mg, 0.56mmol), HOBt (75 mg, 0.56 mmol) and(2S)-2-methoxycarbonylamino-3,3-diphenyl-propionic acid (56 mg, 0.19mmol). The mixture was stirred overnight at room temperature. Theproduct was extracted with ethyl acetate (40 mL) and water (40 mL). Theorganic layer was separated and dried with Na₂SO₄, then evaporated togive 160 mg of crude oil. The residue was purified by flashchromatography with a mixture of eluents hexane/ethyl acetate (2/8). Thetitle compound was obtained as a clear oil in 20% yield (25 mg).

LC-MS: 730.2 (M+H)⁺, 95% pure

¹H NMR (acetone-d₆): δ 0.80-0.97 (m, 9H), 0.97-1.13 (m, 2H), 1.26-1.40(m, 1H), 1.40-1.57 (m, 1H), 2.61-2.73 (m, 1H), 2.86-2.98 (m, 2H),3.00-3.17 (m, 2H), 3.45-3.59 (s, 3H), 3.91-4.00 (m, 1H), 4.24-4.34 (m,1H), 4.34-4.47 (m, 2H), 4.90-4.99 (t, J=9.7, 1H), 6.35-6.44 (m, 1H),6.68-6.79 (d, J=7.9, 1H), 6.91-7.00 (br s, 1H), 7.13-7.22 (m, 2H),7.22-7.31 (m, 3H), 7.35-7.48 (m, 4H), 7.49-7.64 (m, 2H), 7.75-7.84 (m,1H), 8.25-8.36 (m, 1H), 8.76-8.88 (br s, 1H), 9.12-9.26 (br s, 1H).

Example 9 Preparation of (2S,2S)-dimethylamino-acetic acid2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (PL-534) Step A. Preparation of (2S)-dimethylamino-acetic acid6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexylester (XIV, R_(1A)=(CH₃)₂NCH₂—)

This title compound was obtained from(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (intermediate product (VII) of example 1, step D)as described example 15, step A using N,N-dimethylglycine. The clear oilwas obtained in 100% yield (150 mg).

LC-MS: 629.3 (M+H)⁺, 95% pure

¹H NMR (acetone-d₆): δ 0.81-0.95 (d, J=6.1, 6H), 1.18-1.30 (m, 2H),1.32-1.43 (s, 9H), 1.43-1.52 (s, 8H), 1.52-1.62 (m, 1H), 1.93-2.00 (m,1H), 2.19-2.29 (s, 4H), 2.69-2.80 (m, 4H), 2.90-3.05 (m, 6H), 3.60-3.65(m, 1H), 3.85-3.97 (m, 1H), 3.98-4.08 (m, 1H), 4.08-4.14 (m, 1H),5.78-5.88 (m, 1H), 7.68-7.80 (m, 3H), 8.80-8.88 (br s, 1H).

Step B. Preparation of (2S)-dimethylamino-acetic acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (XV,R_(1A)=(CH₃)₂NCH₂—)

The title derivative was prepared from (2S)-dimethylamino-acetic acid6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexylester as described in example 15, step B. The final product (100 mg) wasused as such in the next step.

LC-MS: 429.3 (M+H)⁺, 90% pure

Step C. Preparation of (2S,2S)-dimethylamino-acetic acid2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (PL-534)

This title compound was prepared from (2S)-dimethylamino-acetic acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester asdescribed in example 15, step C. The crude product was purified byLC-preparative. The final compound was obtained in 10% yield (10 mg).

LC-MS: 710.3 (M+H)⁺, 92% pure

¹H NMR (acetone-d₆): δ 0.81-0.98 (m, 12H), 1.14-1.30 (m, 2H), 1.31-1.45(m, 1H), 2.58-2.77 (m, 2H), 2.79-2.90 (m, 2H), 3.42-3.56 (s, 3H),3.75-3.85 (m, 1H), 3.99-4.17 (m, 3H), 4.23-4.35 (m, 1H), 4.36-4.45 (m,1H), 4.86-4.96 (m, 1H), 6.33-6.42 (m, 1H), 6.74-6.83 (m, 1H), 6.85-6.90(m, 1H), 7.12-7.22 (m, 3H), 7.23-7.31 (m, 4H), 7.31-7.44 (m, 5H),7.47-7.55 (m, 1H), 7.73-7.80 (m, 1H).

Example 10 Preparation of (2S,2S)-2-amino-3-methyl-butyric acid2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (PL-530) Step A. Preparation of(2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexylester (XIV, R_(1A)=(CH₃)₂CHCH(NH₂)—)

This title compound was obtained from(1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamicacid tert-butyl ester (intermediate product (VII) of example 1, step D)as described in example 15, step A using(2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid. The crude productwas purified by flash chromatography eluting with a mixture ofhexane/ethyl acetate (1/1). The yield obtained was 100% (150 mg).

LC-MS: 777.3 (M+H)⁺, 95% pure

¹H NMR (acetone-d₆): δ 0.80-1.00 (m, 14), 1.13-1.28 (s, 2H), 1.30-1.44(s, 11H), 1.45-1.56 (s, 10), 1.58-1.67 (m, 1H), 2.87-3.04 (m, 4H),3.84-3.97 (m, 1H), 3.97-4.12 (m, 2H), 4.12-4.21 (m, 1H), 4.99-5.14 (m,2H), 5.78-5.89 (m, 1H), 6.38-6.52 (m, 1H), 7.24-7.34 (m, 1H), 7.34-7.41(m, 2H), 7.65-7.83 (m, 4H), 8.77-8.86 (m, 1H).

Step B. Preparation of (2S)-benzyloxycarbonylamino-3-methyl-butyric acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester (XV,R_(1A)=(CH₃)₂CHCH(NH₂)—)

This derivative was prepared from(2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid6-tert-butoxycarbonylamino-2-[(4-tert-butoxycarbonylamino-benzenesulfonyl)-isobutyl-amino]-hexylester (product of step A) as described in example 15, step B. The finalcompound was obtained in quantitative yield (110 mg) and used for thenext step without purification.

LC-MS: 577.3 (M+H)⁺, 90% pure

Step C. Preparation of (2S,2S)-2-benzyloxycarbonylamino-3-methyl-butyricacid2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester

The title compound was obtained from(2S)-benzyloxycarbonylamino-3-methyl-butyric acid6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl ester(product of step B) as described in example 15, step C. The clear oilwas obtained in 86% yield (120 mg).

LC-MS: 858.3 (M+H)⁺, 95% pure

Step D. Preparation of (2S,2S)-2-amino-3-methyl-butyric acid2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (PL-530)

To a stirred solution of(2S,2S)-2-benzyloxycarbonylamino-3-methyl-butyric acid2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-(2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-hexylester (step C, 120 mg, 0.14 mmol) in anhydrous THF (8 mL), undernitrogen atmosphere, was added palladium 10% wt. on activated carbon(160 mg). The mixture was reacted under hydrogen atmosphere overnight,at room temperature. The solution was filtered and the palladium oncarbon was washed with THF (50 mL). The solvent was evaporated and theresidue (110 mg) was purified by flash chromatography using ethylacetate as the eluent. The clear oil was obtained in 47% yield (47 mg).

LC-MS: 796.4 (M+H)⁺, 95% pure

¹H NMR (acetone-d₆): δ 0.84-0.97 (m, 12H), 0.97-1.08 (m, 2H), 1.27-1.43(m, 3H), 1.49-1.62 (m, 4H), 1.80-1.93 (m, 1H), 1.94-2.00 (m, 1H),2.36-2.46 (m, 1H), 2.58-2.74 (m, 2H), 2.86-2.96 (m, 3H), 2.99-3.10 (m,2H), 3.46-3.52 (s, 3H), 3.52-3.60 (m, 2H), 3.75-3.87 (m, 2H), 3.95-4.04(m, 1H), 4.10-4.18 (m, 1H), 4.37-4.44 (m, 1H), 4.89-4.97 (m, 1H),5.40-5.48 (m, 1H), 6.30-6.40 (m, 1H), 6.76-6.83 (d, J=8.2, 1H),6.87-7.03 (m, 2H), 7.14-7.22 (m, 1H), 7.23-7.34 (m, 3H), 7.35-7.45 (m,4H), 7.50-7.56 (m, 1H), 7.57-7.65 (m, 1H).

Bioavailability of the Compounds

To assess the extent of in vivo cleavage of the phosphate group from theputative compounds, PL-100, PL-462 (based on PL-100), PL-337 and PL-515(based on PL-337) compounds were administered po (50 mg/kg) to maleSprague-Dawley rats and their plasma concentration measured at differenttime intervals post-administration.

PL100 is an active ingredient (protease inhibitor) of the followingformula;

PL-337 is an active ingredient (protease inhibitor) of the followingformula;

The active ingredient has been shown to be efficient against an HIV-1aspartyl protease (U.S. Pat. No. 6,632,816). The active ingredients alsopresent potent antiviral activity when tested on non-mutated HIV-1 viralstrain (NL4.3 as the wild type virus) as well as several mutant strains.

All test articles (PL-100, PL-462, PL-337 and PL-515) were prepared indifferent vehicle at the final concentration of 25 mg/mL. The vehiclecomposition is as follows: (1) 20% ethanol; 50% propylene glycol; 0.05%w/v Tween 20 and water (Mix); (2) PBS buffer (PBS).

Test articles were administered to male Sprague-Dawley rats at a singleoral dose of 50 mg/kg. Each article was tested in three rats. Bloodsamples (0.2-0.3 mL) were collected at the post-dose time of 10, 20, 40,60, 120, 180 and 360 minutes. The harvested blood was centrifuged toisolate plasma. The resulting plasma was separated and stored at −70° C.

Plasma samples together with standards and quality control samples weretreated to precipitate proteins, then analyzed by HPLC-MS, for thepresence of PL-462, PL-100, PL-515 and PL-337.

TABLE 1 PL-462 PL-100 PL-515 PL-337 Compound (Ex. No. 2) (Ex. No. 1-F)(Ex. No. 13) (Ex. No. 13-A) Vehicle PBS Mix PBS Mix Number of rats 3 3 33 Dose (mg/Kg) 50 po 50 po 50 po 50 po AUC (μg/hr*ml) 0.816 ± 0.2950.675 ± 0.171 1.075 ± 0.625 1.180 ± 0.196 (PL-100, (PL-337, detected)detected) Cmax (nM) 330 ± 109 498 ± 203 545 ± 215 681 ± 131 Tmax (min)93 ± 60 40 ± 16 87 ± 60 60 ± 15 50 mg/Kg PL-462 = 43 mg/Kg PL-100 50mg/Kg PL-515 = 43 mg/Kg PL-337

The results demonstrate that PL-462 and PL-515 compounds may bedelivered orally in aqueous solutions. None of the PL-462 and PL-515compounds, delivered as aqueous solutions, are detected in the bloodsamples, which suggests rapid metabolism to PL-100 and PL-337 the parentdrugs.

Aqueous dosing of PL-462 and PL-515 solutions showed equivalent toslightly superior delivery of PL-100 and PL-337 compared to non-aqueousformulations of PL-100 and PL-337.

Based on these results, all the phosphorylated compounds described inthe present invention will demonstrate similar pharmacokineticproperties.

Partition coefficient (LogP) of selected compounds and the correspondingHIV protease inhibitors (drug) are as follow:

TABLE Compounds LogP Corresponding drugs LogP PL-461 (or PL-462) −1.2PL-100 3.6 PL-515 −0.75 PL-337 3.8

The LogP were measured in a standard fashion by dissolving 1 mg ofcompound in 0.8 mL of each octanol and phosphate buffer pH 7.4 (0.04 MKHPO₄). The concentration of the compounds in the phases was detected byLC-MS. This test demonstrates the solubility of the compounds atphysiological pH. The LogP obtained show that the compounds are highlysoluble as compare to the corresponding drugs.

The compounds listed in Table 3 were prepared by following scheme 1, 1A,2, 3, 4 or 5; and more particularly as described in each example listedabove. The numbers of the compounds listed in Table 3 (Ex. No.)corresponds to the example numbers presented above.

TABLE 3 Structures of lysine based compounds in accordance with thepresent invention I

D, L, DL Ex. No (PL-#) X Y n R₁ R₂ R₃ R₆ X′/Y′ R, S, RS 1 (PL-461) 4-NH₂H 4 (HO)₂P(O) (C₆H₅)₂CH CH₃O—CO iso-butyl H/H S,S 2 (PL-462) 4-NH₂ H 4(NaO)₂P(O) (C₆H₅)₂CH CH₃O—CO iso-butyl H/H S,S 3 (PL-507) 4-NH₂ H 4(HO)₂P(O) Naphthyl-2-CH₂ CH₃O—CO iso-butyl H/H S,S 4 (PL-498) 4-NH₂ H 4(HO)₂P(O) Naphthyl-1-CH₂ 4-morpholine- iso-butyl H/H S,S CO 5 (PL-504)4-NH₂ H 4 (HO)₂P(O) (C₆H₅)₂CH CH₃CO iso-butyl H/H S,S 6 (PL-515) 4-NH₂3-F 4 (HO)₂P(O) (C₆H₅)₂CH CH₃O—CO iso-butyl H/H S,S 7 (PL-521) 4-NH₂ H 4CH₃CO (C₆H₅)₂CH CH₃O—CO iso-butyl H/H S,S 8 (PL-520) 4-NH₂ H 43-Pyridyl-CO (C₆H₅)₂CH CH₃O—CO iso-butyl H/H S,S 9 (PL-534) 4-NH₂ H 4(CH₃)₂NCH₂CO (C₆H₅)₂CH CH₃O—CO iso-butyl H/H S,S 10 (PL-530) 4-NH₂ H 4(CH₃)₂CHCH(NH₂)CO (C₆H₅)₂CH CH₃O—CO iso-butyl H/H S,S

1.-80. (canceled)
 81. A method for treating or preventing an HIVinfection or for delaying the appearance of AIDS, which comprisesadministering a compound of Formula II,

or a pharmaceutically acceptable salt thereof, optionally in combinationwith another HIV antiviral or anti-retroviral agent to a mammal in needthereof, wherein n is 3 or 4, wherein X and Y, the same or different,are selected from the group consisting of H, a straight alkyl group of 1to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, acycloalkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN,—NO₂, —NR₄R₅, —NHCOR₄, —OR₄, —SR₄, —COOR₄, —COR₄, and —CH₂OH or X and Ytogether define an alkylenedioxy group selected from the groupconsisting of a methylenedioxy group of formula —OCH₂O— and anethylenedioxy group of formula —OCH₂CH₂O—, wherein R₆ is selected fromthe group consisting of a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms and a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, wherein R₃ is selected from thegroup consisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, and a group of formula R_(3A)—CO—, R_(3A) being selectedfrom the group consisting of a straight or branched alkyl group of 1 to6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, acycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl partthereof and 1 to 3 carbon atoms in the alkyl part thereof, an alkyloxygroup of 1 to 6 carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃,—CH₂CF₃, —CH₂CH₂CF₃, pyrrolidinyl, piperidinyl, 4-morpholinyl, CH₃O₂C—,CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl, 4-hydroxyphenyl,4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—, (CH₃CH₂CH₂)₂N—,HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—, 2-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₄R₅, —NHCOR₄, —OR₄, —SR₄,—COOR₄, —COR₄ and —CH₂OH, wherein R₄ and R₅, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms, wherein R₂ is selected from thegroup consisting of a diphenylmethyl group of formula IV,

a naphthyl-1-CH₂— group of formula V,

a naphthyl-2-CH₂— group of formula VI,

a biphenylmethyl group of formula VII,

and an anthryl-9-CH₂— group of formula VIII,

and wherein R₁ is selected from the group consisting of (HO)₂P(O),(MO)₂P(O) and a group of formula R_(1A)—CO—, wherein M is an alkalimetal or alkaline earth metal, wherein R_(1A) is selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—,(CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl,2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula


82. A method according to claim 81, wherein the compound is Formula IIa,

or a pharmaceutically acceptable salt thereof.
 83. A method according toclaim 82, wherein R₆ is iso-butyl.
 84. A method according to claim 83,wherein n is
 4. 85. A method according to claim 84, wherein R₁ is(HO)₂P(O) or (NaO)₂P(O).
 86. A method according to claim 81, wherein thecompound is Formula IIb,

or a pharmaceutically acceptable salt thereof.
 87. A method according toclaim 86, wherein R₆ is iso-butyl.
 88. A method according to claim 87,wherein n is
 4. 89. A method according to claim 88, wherein R₁ is(HO)₂P(O) or (NaO)₂P(O).
 90. A method according to claim 81, wherein thecompound is Formula IIc,

or a pharmaceutically acceptable salt thereof.
 91. A method according toclaim 90, wherein R₆ is iso-butyl.
 92. A method according to claim 91,wherein n is
 4. 93. A method according to claim 92, wherein R₁ is(HO)₂P(O) or (NaO)₂P(O).
 94. A method according to claim 85, wherein thecompound is:(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexacarbomoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester or a pharmaceutically acceptable salt thereof; or(1S,5S)-(1-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexacarbomoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester or a pharmaceutically acceptable salt thereof.
 95. Amethod according to claim 94, wherein the compound is(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexacarbomoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester sodium salt.
 96. A method according to claim 94,wherein the compound is(1S,5S)-(1-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexacarbomoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester sodium salt.
 97. A method according to claim 81,wherein the compound of Formula II is administered in combination withan HIV antiviral or anti-retroviral agent that targets attachment to thecell receptor and cell entry, reverse transcription or viral DNAintegration.
 98. A method according to claim 82, wherein the compound ofFormula IIa is administered in combination with an HIV antiviral oranti-retroviral agent that targets attachment to the cell receptor andcell entry, reverse transcription or viral DNA integration.
 99. A methodaccording to claim 98, wherein the compound is(1S,5S)-(1-{5-[(4-amino-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexacarbomoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester or a pharmaceutically acceptable salt thereof; or(1S,5S)-(1-{5-[(4-amino-3-fluoro-benzenesulfonyl)-isobutyl-amino]-6-phosphonooxy-hexacarbomoyl}-2,2-diphenyl-ethyl)-carbamicacid methyl ester or a pharmaceutically acceptable salt thereof.
 100. Amethod according to claim 81, wherein the compound of Formula II isadministered in combination with another HIV protease inhibitor.
 101. Amethod according to claim 82, wherein the compound of Formula IIa isadministered in combination with another HIV protease inhibitor.
 102. Amethod for treating or preventing viral infections that use aspartylprotease in their life cycle, which comprises administering a compoundof Formula II,

or a pharmaceutically acceptable salt thereof, wherein n is 3 or 4,wherein X and Y, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₄R₅, —NHCOR₄,—OR₄, —SR₄, —COOR₄, —COR₄, and —CH₂OH or X and Y together define analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O— and an ethylenedioxy group offormula —OCH₂CH₂O—, wherein R₆ is selected from the group consisting ofa straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms and a cycloalkylalkyl group having 3 to 6 carbonatoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in thealkyl part thereof, wherein R₃ is selected from the group consisting ofH, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl groupof 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and agroup of formula R_(3A)—CO—, R_(3A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, pyrrolidinyl, piperidinyl, 4-morpholinyl, CH₃O₂C—,CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl, 4-hydroxyphenyl,4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—, (CH₃CH₂CH₂)₂N—,HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—, 2-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₄R₅, —NHCOR₄, —OR₄, —SR₄,—COOR₄, —COR₄ and —CH₂OH, wherein R₄ and R₅, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms, wherein R₂ is selected from thegroup consisting of a diphenylmethyl group of formula IV,

a naphthyl-1-CH₂— group of formula V,

a naphthyl-2-CH₂— group of formula VI,

a biphenylmethyl group of formula VII,

and an anthryl-9-CH₂— group of formula VIII,

and wherein R₁ is selected from the group consisting of (HO)₂P(O),(MO)₂P(O) and a group of formula R_(1A)—CO—, wherein M is an alkalimetal or alkaline earth metal, wherein R_(1A) is selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—HO₂CCH₂—,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—,(CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl,2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula


103. A method according to claim 102, wherein said viral infection isselected from the group consisting of simian immunodeficiency virus,HIV-2, HTLV-I and HTLV-II infections.
 104. A method of inhibiting ahuman aspartyl protease, which comprises administering a compound ofFormula II,

or a pharmaceutically acceptable salt thereof, wherein n is 3 or 4,wherein X and Y, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —OCF₃, —CN, —NO₂, —NR₄R₅, —NHCOR₄,—OR₄, —SR₄, —COOR₄, —COR₄, and —CH₂OH or X and Y together define analkylenedioxy group selected from the group consisting of amethylenedioxy group of formula —OCH₂O— and an ethylenedioxy group offormula —OCH₂CH₂O—, wherein R₆ is selected from the group consisting ofa straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of3 to 6 carbon atoms and a cycloalkylalkyl group having 3 to 6 carbonatoms in the cycloalkyl part thereof and 1 to 3 carbon atoms in thealkyl part thereof, wherein R₃ is selected from the group consisting ofH, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl groupof 3 to 6 carbon atoms, a cycloalkyl group of 3 to 6 carbon atoms, and agroup of formula R_(3A)—CO—, R_(3A) being selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, tetrahydro-3-furanyloxy, —CH₂OH, —CF₃, —CH₂CF₃,—CH₂CH₂CF₃, pyrrolidinyl, piperidinyl, 4-morpholinyl, CH₃O₂C—,CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—, 3-hydroxyphenyl, 4-hydroxyphenyl,4-CH₃OC₆H₄CH₂—, CH₃NH—, (CH₃)₂N—, (CH₃CH₂)₂N—, (CH₃CH₂CH₂)₂N—,HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, C₆H₅CH₂O—, 2-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl-, 2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,1-isoquinolyl, 3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula

wherein X′ and Y′, the same or different, are selected from the groupconsisting of H, a straight alkyl group of 1 to 6 carbon atoms, abranched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to6 carbon atoms, F, Cl, Br, I, —CF₃, —NO₂, —NR₄R₅, —NHCOR₄, —OR₄, —SR₄,—COOR₄, —COR₄ and —CH₂OH, wherein R₄ and R₅, the same or different, areselected from the group consisting of H, a straight alkyl group of 1 to6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, and acycloalkyl group of 3 to 6 carbon atoms, wherein R₂ is selected from thegroup consisting of a diphenylmethyl group of formula IV,

a naphthyl-1-CH₂— group of formula V,

a naphthyl-2-CH₂— group of formula VI,

a biphenylmethyl group of formula VII,

and an anthryl-9-CH₂— group of formula VIII,

and wherein R₁ is selected from the group consisting of (HO)₂P(O),(MO)₂P(O) and a group of formula R_(1A)—CO—, wherein M is an alkalimetal or alkaline earth metal, wherein R_(1A) is selected from the groupconsisting of a straight or branched alkyl group of 1 to 6 carbon atoms,a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl grouphaving 3 to 6 carbon atoms in the cycloalkyl part thereof and 1 to 3carbon atoms in the alkyl part thereof, an alkyloxy group of 1 to 6carbon atoms, —CH₂OH, CH₃O₂C—, CH₃O₂CCH₂—, Acetyl-OCH₂CH₂—, HO₂CCH₂—,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, (CH₃)₂NCH₂—,(CH₃)₂CHCH(NH₂)—, HOCH₂CH₂NH—, CH₃OCH₂O—, CH₃OCH₂CH₂O—, 2-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-1,4-dihydro-3-pyridyl,2-pyrazinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl,3-isoquinolyl, 2-quinoxalinyl, a phenyl group of formula

a picolyl group selected from the group consisting of

a picolyloxy group selected from the group consisting of

a substituted pyridyl group selected from the group consisting of

and a group of formula